11-118373524-C-G

Position:

chr11-118373524-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001204077.2(UBE4A):c.955C>G(p.Pro319Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,614,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

UBE4A
NM_001204077.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51

Variant links:

Genes affected

UBE4A (HGNC:12499): (ubiquitination factor E4A) This gene encodes a member of the U-box ubiquitin ligase family. The encoded protein is involved in multiubiquitin chain assembly and plays a critical role in chromosome condensation and separation through the polyubiquitination of securin. Autoantibodies against the encoded protein may be markers for scleroderma and Crohn's disease. A pseudogene of this gene is located on the long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2011]

UBE4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0062937737).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00216 (329/152286) while in subpopulation AFR AF= 0.00755 (314/41566). AF 95% confidence interval is 0.00687. There are 1 homozygotes in gnomad4. There are 148 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
UBE4A	NM_001204077.2 linkuse as main transcript	c.955C>G	p.Pro319Ala	missense_variant	8/20	ENST00000252108.8	NP_001191006.1
UBE4A	NM_004788.4 linkuse as main transcript	c.976C>G	p.Pro326Ala	missense_variant	8/20		NP_004779.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE4A	ENST00000252108.8 linkuse as main transcript	c.955C>G	p.Pro319Ala	missense_variant	8/20	1	NM_001204077.2	ENSP00000252108	P1	Q14139-1
UBE4A	ENST00000431736.6 linkuse as main transcript	c.976C>G	p.Pro326Ala	missense_variant	8/20	1		ENSP00000387362		Q14139-2

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

327

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00753

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000649

AC:

163

AN:

251148

Hom.:

AF XY:

0.000457

AC XY:

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.00720

Gnomad AMR exome

AF:

0.000926

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000969

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000226

AC:

331

AN:

1461768

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

134

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00615

Gnomad4 AMR exome

AF:

0.000917

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.00216

AC:

329

AN:

152286

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00755

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000381

Hom.:

Bravo

AF:

0.00252

ESP6500AA

AF:

0.00773

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000774

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 06, 2024

Variant summary: UBE4A c.976C>G (p.Pro326Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 251148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.976C>G in individuals affected with Neurodevelopmental Disorder With Hypotonia And Gross Motor And Speech Delay and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.046

T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.20

Sift

Benign

0.80

T;T

Sift4G

Benign

0.76

T;T

Polyphen

0.98

D;D

Vest4

0.55

MVP

0.093

MPC

0.60

ClinPred

0.22

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.058

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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