rs114925667

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PP5_StrongBP4BS1_Supporting

The ENST00000356232.10(UBA5):c.1111G>A(p.Ala371Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,601,206 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (★★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 6 hom. )

Consequence

UBA5
ENST00000356232.10 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 8.94

Variant links:

Genes affected

UBA5 (HGNC:23230): (ubiquitin like modifier activating enzyme 5) This gene encodes a member of the E1-like ubiquitin-activating enzyme family. This protein activates ubiquitin-fold modifier 1, a ubiquitin-like post-translational modifier protein, via the formation of a high-energy thioester bond. Alternative splicing results in multiple transcript variants. A pseudogene of this gene has been identified on chromosome 1. [provided by RefSeq, Feb 2016]

UBA5 links:

NPHP3-ACAD11 (HGNC:):

NPHP3-ACAD11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP5

Variant 3-132675903-G-A is Pathogenic according to our data. Variant chr3-132675903-G-A is described in ClinVar as [other]. Clinvar id is 265745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=14, Pathogenic_low_penetrance=1}. Variant chr3-132675903-G-A is described in Lovd as [Pathogenic]. Variant chr3-132675903-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.012316883). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00162 (246/152042) while in subpopulation NFE AF= 0.00219 (149/67914). AF 95% confidence interval is 0.00191. There are 1 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBA5	NM_024818.6 linkuse as main transcript	c.1111G>A	p.Ala371Thr	missense_variant	11/12	ENST00000356232.10	NP_079094.1
NPHP3-ACAD11	NR_037804.1 linkuse as main transcript	n.3995+6011C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBA5	ENST00000356232.10 linkuse as main transcript	c.1111G>A	p.Ala371Thr	missense_variant	11/12	1	NM_024818.6	ENSP00000348565	P1	Q9GZZ9-1

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

246

AN:

151924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00577

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00219

Gnomad OTH

AF:

0.000961

GnomAD3 exomes

AF:

0.00187

AC:

455

AN:

243374

Hom.:

AF XY:

0.00194

AC XY:

256

AN XY:

131692

show subpopulations

Gnomad AFR exome

AF:

0.000440

Gnomad AMR exome

AF:

0.000649

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00585

Gnomad NFE exome

AF:

0.00258

Gnomad OTH exome

AF:

0.00237

GnomAD4 exome

AF:

0.00281

AC:

4070

AN:

1449164

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

1938

AN XY:

720326

show subpopulations

Gnomad4 AFR exome

AF:

0.000851

Gnomad4 AMR exome

AF:

0.000761

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00536

Gnomad4 NFE exome

AF:

0.00324

Gnomad4 OTH exome

AF:

0.00214

GnomAD4 genome

AF:

0.00162

AC:

246

AN:

152042

Hom.:

Cov.:

AF XY:

0.00176

AC XY:

131

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.000603

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00577

Gnomad4 NFE

AF:

0.00219

Gnomad4 OTH

AF:

0.000951

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00139

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00184

AC:

223

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 16, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	UBA5: PM3:Very Strong, PM2:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2024	Published functional studies demonstrate a slightly reduced activity on UFM1 activation with an attenuated ability to transfer the activated UFM1 to UFC1 (PMID: 27545674, 27545681, 27926783); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30287594, 27545681, 27545674, 27926783, 28965491, 2179706, 32149490, 31980526, 34426522, 34299007, 33811063, 33726816, 34588452, 38079206, 36680403, 37947621, 38328212, 37432431, 37838930, 37945409) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2024	- -
Pathogenic, low penetrance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 371 of the UBA5 protein (p.Ala371Thr). This variant is present in population databases (rs114925667, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with UBA5-related epileptic encephalopathy (PMID: 27545674, 27545681, 28965491, 29286531). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (PMID: 27545681, 28965491). ClinVar contains an entry for this variant (Variation ID: 265745). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects UBA5 function (PMID: 27545674, 27545681). In summary, this variant has been reported as a hypomorphic variant that partially decreases UBA5 protein function. This variant causes UBA5-related epileptic encephalopathy when in trans from a null variant; however, homozygous individuals appear to be clinically unaffected. For these reasons, this variant has been classified as Pathogenic (low penetrance). -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Developmental and epileptic encephalopathy, 44

Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 19, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with developmental and epileptic encephalopathy 44 (MIM#617132). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (244 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated transthiolation domain (PMID: 27545674). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and is consistently reported in compound heterozygous patients with early-onset epileptic encephalopathy, where homozygous individuals are not affected (ClinVar, Decipher, PMID: 27545681, PMID: 27545674). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been functionally established as a hypomorphic allele, resulting in a modest reduction in enzyme activity (PMID: 27545681, PMID: 27545674). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Ala371Thr variant was identified in the compound heterozygous state by our study in one individual with Epileptic Encephalopathy. The p.Ala371Thr variant has been reported in the literature in 11 individuals across 7 families (Colin 2016, Muona 2016). Of note, all of these individuals were compound heterozygous with a loss-of-function variant. This variant has been identified in 0.58% (148/25672, no homozygotes) of Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs114925667). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is pathogenic. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_198329.2:c.943G>A in the UBA5 gene has an allele frequency of 0.006 in European (Finnish) subpopulation in the gnomAD database. This variant also known as A371T in literature. This variant in compound heterozygosity with another pathogenic variant has been previously reported as disease causing in multiple unrelated patients affected with early infantile epileptic encephalopathy (PMID: 27545681). Functional studies of A371T indicate that it results in slightly reduced activity on UFM1 activation with an attenuated ability to transfer the activated UFM1 to UFC1 (PMID: 27545681, 27545674). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP Criteria applied: PM3_Strong, PS3, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Feb 15, 2017	A heterozygous c.1111G>A (p.A371T) pathogenic variant in the UBA5 gene was detected in this individual. This variant in compound heterozygosity with another pathogenic variant has been previously reported as disease causing in multiple unrelated patients affected with early infantile epileptic encephalopathy [PMID 27545681, 27545681]. This variant in homozygous state has also been previously reported in one individual who is free of any neurological disorder in his fifties. In combination with data from in vitro functional studies, the c.1111G>A (p.A371T) variant was suggested to act as a hypomorphic allele [PMID 27545681]. ACMG criteria applied: PS1, PS3, PM2, PM3, PP3, PP4, BS2. -
Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Apr 11, 2022	This sequence variant is a single nucleotide substitution (G>A) that results in an alanine to threonine amino acid substitution at position 371 of the UBA5 protein. This is a previously reported variant (ClinVar) that is found in control population datasets (gnomAD database 517/274744 alleles or 0.18%) at a level consistent with carrier status for an Autosomal recessive inheritance disease. This variant is observed as a compound heterozygous variant in individuals with UBA5-related disease and segregates with affected family members (PMID: 29286531, 28965491, 27545674). Bioinformatic tools predict that this variant would be damaging and the Ala371 residue is highly conserved across the vertebrate species examined. Functiol alysis suggests that this is a hypomorphic allele in which the protein produced by this variant retains its interaction with UFM1 but reduces the trans-esterification of UFM1 to UFC1 (PMID: 27545681, 33811063). Consistent with this, individuals homozygous for this variant are reported to be uffected (PMID: 28965491). Because this variant is reported as compound heterozygous in affected individuals for a recessive disorder, we consider this variant to be pathogenic. ACMG Criteria: PM3, PP1, PS3 -

Spinocerebellar ataxia, autosomal recessive 24;C4310700:Developmental and epileptic encephalopathy, 44

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	May 21, 2018	This variant has been described in multiple other cases in the literature and has been shown to be hypomorphic. -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 28, 2022	- -

UBA5-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2023	Variant summary: UBA5 c.1111G>A (p.Ala371Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 243374 control chromosomes, predominately at a frequency of 0.0059 in the Finnish European subpopulation in the gnomAD database. However, it has been reported as a hypomorphic allele, expected to result in disease only when found in trans with a pathogenic variant (e.g. Colin_2016, Muona_2016). Indeed, c.1111G>A has been reported in the literature in the compound heterozygous state in trans with a pathogenic variant in multiple individuals affected with Early Onset Encephalopathy from at least seven different families and has been found to segregate with disease (e.g. Colin_2016, Muona_2016). It has also been identified in a homozygous individual who was unaffected, having no reported neurological symptoms at over 50 years of age (Muona_2016). These data indicate that the variant is very likely to be a hypomorphic allele associated with disease. Experimental studies evaluating an impact on protein function found that the variant results in decreased E1 activity compared to the wild-type protein, but retains the ability to form the intermmediate between UFC1 and UFM1, although at a slower reaction rate, further supporting that the variant functions as a hypomorphic allele (e.g. Colin_2016, Muona_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27545681, 27545674). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=12)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 14, 2023	The UBA5 c.1111G>A variant is predicted to result in the amino acid substitution p.Ala371Thr. This variant has been reported in the compound heterozygous state, segregating with autosomal recessive early infantile epileptic encephalopathy in several patients (Muona et al. 2016. PubMed ID: 27545674; Colin et al. 2016. PubMed ID: 27545681; Arnadottir et al. 2017. PubMed ID: 28965491; Tumienė et al. 2017. PubMed ID: 29286531). This variant was also reported in the homozygous state in three Icelandic individuals who had no signs of neurological disease, suggesting that p.Ala371Thr acts as a hypomorphic variant (Arnadottir et al 2017. PubMed ID: 28965491). This variant is interpreted as likely pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 06, 2018

The p.Ala371Thr variant in UBA5 has been reported in a compound heterozygous sta te with a loss-of-function variant in 6 probands with early infantile epileptic encephalopathy and segregated with disease in 4 additional affected relatives (M uona 2016, Colin 2016). Two additional probands and one additional sib have been identified with either missense or silent with suspected splice effects in tran s with this variant (Muona 2016, Arnadottir 2017). While several homozygous indi viduals without neurological symptoms into adulthood have been reported in the l iterature (Colin 2016, Arnadottir 2017), functional assays demonstrating an inte rmediate enzyme activity compared to loss-of-function variants and controls supp ort the conclusion that this variant is a hypomorphic allele with a low risk of phenotypic effect in a homozygous state (Muona 2016, Colin 2016). In summary, th is variant meets criteria to be classified as pathogenic for early infantile epi leptic encephalopathyin an autosomal recessive manner based upon case counts, se gregation studies, and functional evidence. ACMG/AMP Criteria applied: PM3_VeryS trong, PP1_Moderate, PS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

.;D;.;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;.

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.4

.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0080

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.70

MVP

0.58

MPC

0.67

ClinPred

0.071

GERP RS

5.4

Varity_R

0.49

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over