NM_024818.6:c.1111G>A

Variant names:

• chr3-132675903-G-A
• rs114925667
• NM_024818.6:c.1111G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 12P and 6B. PS3 PP5_Very_Strong BP4 BS1_Supporting BS2

The NM_024818.6(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 Likely pathogenic,low penetrance (★★). ClinVar reports functional evidence for this variant: "SCV000746629: 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]." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (6 hom.)
• Consequence: UBA5 NM_024818.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:28
• Conservation: PhyloP100: 8.94
• Publications: 26 publications found

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]

NPHP3-ACAD11 (HGNC:48351): (NPHP3-ACAD11 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring NPHP3 (nephronophthisis 3, adolescent) and ACAD11 (acyl-CoA dehydrogenase family, member 11) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000746629: 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].; SCV001142330: 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).; SCV003922011: This variant has been functionally established as a hypomorphic allele, resulting in a modest reduction in enzyme activity (PMID: 27545681, 27545674).; SCV005397468: 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).; SCV006584443: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 27545674, 27545681)."; SCV000616912: 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); SCV001206482: Experimental studies have shown that this missense change affects UBA5 function (PMID: 27545674, 27545681).; SCV000966807: "functional assays demonstrating an intermediate enzyme activity compared to loss-of-function variants and controls support the conclusion that this variant is a hypomorphic allele with a low risk of phenotypic effect in a homozygous state (Muona 2016, Colin 2016)."; SCV004029717: 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). PMID: 27545681, 27545674; SCV005900668: Results from an in vitro study provide evidence that this variant is hypomorphic and leads to reduced thioester formation activity (PMID: 27545674).
• PP5: Variant 3-132675903-G-A is Pathogenic according to our data. Variant chr3-132675903-G-A is described in ClinVar as Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance. ClinVar VariationId is 265745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024818.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA5	NM_024818.6	MANE Select	c.1111G>A	p.Ala371Thr	missense	Exon 11 of 12	NP_079094.1	Q9GZZ9-1
	UBA5	NM_001320210.2		c.943G>A	p.Ala315Thr	missense	Exon 11 of 12	NP_001307139.1	Q9GZZ9-2
	UBA5	NM_198329.4		c.943G>A	p.Ala315Thr	missense	Exon 11 of 12	NP_938143.1	Q9GZZ9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA5	ENST00000356232.10	TSL:1 MANE Select	c.1111G>A	p.Ala371Thr	missense	Exon 11 of 12	ENSP00000348565.4	Q9GZZ9-1
	UBA5	ENST00000494238.6	TSL:1	c.943G>A	p.Ala315Thr	missense	Exon 11 of 12	ENSP00000418807.2	Q9GZZ9-2
	NPHP3-ACAD11	ENST00000632629.1	TSL:2	c.635+6011C>T		intron	N/A	ENSP00000488520.1	A0A0J9YXS1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 246 AN: 151924 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.00187 AC: 455 AN: 243374 AF XY: 0.00194

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 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.: 6 Cov.: 30 AF XY: 0.00269 AC XY: 1938 AN XY: 720326

African (AFR) AF: 0.000851 AC: 28 AN: 32902

American (AMR) AF: 0.000761 AC: 32 AN: 42038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25624

East Asian (EAS) AF: 0.00 AC: 0 AN: 39462

South Asian (SAS) AF: 0.00 AC: 0 AN: 83214

European-Finnish (FIN) AF: 0.00536 AC: 285 AN: 53158

Middle Eastern (MID) AF: 0.000748 AC: 4 AN: 5348

European-Non Finnish (NFE) AF: 0.00324 AC: 3593 AN: 1107518

Other (OTH) AF: 0.00214 AC: 128 AN: 59900

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152042 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74328

African (AFR) AF: 0.000603 AC: 25 AN: 41488

American (AMR) AF: 0.000589 AC: 9 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00577 AC: 61 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 67914

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.00188 Hom.: 2

Bravo AF: 0.00139

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00184 AC: 223

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Developmental and epileptic encephalopathy, 44 (10)
10	-	-	not provided (10)
3	-	-	Spinocerebellar ataxia, autosomal recessive 24;C4310700:Developmental and epileptic encephalopathy, 44 (3)
3	-	-	UBA5-related disorder (3)
1	-	-	Developmental and epileptic encephalopathy (1)
1	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		8.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.70
MVP		0.58
MPC		0.67
ClinPred		0.071	T
GERP RS		5.4
Varity_R		0.49
gMVP		0.60
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs114925667; hg19: chr3-132394747;