X-119574743-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_003336.4(UBE2A):c.32G>A(p.Arg11Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: UBE2A NM_003336.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.16

Genes affected

UBE2A (HGNC:12472): (ubiquitin conjugating enzyme E2 A) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin-protein ligases. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. This enzyme is required for post-replicative DNA damage repair, and may play a role in transcriptional regulation. Mutations in this gene are associated with cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain UBC core (size 146) in uniprot entity UBE2A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_003336.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765
• PP5: Variant X-119574743-G-A is Pathogenic according to our data. Variant chrX-119574743-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29993.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE2A	NM_003336.4	c.32G>A	p.Arg11Gln	missense_variant	1/6	ENST00000371558.7
UBE2A	NM_181762.3	c.32G>A	p.Arg11Gln	missense_variant	1/5
UBE2A	NM_001282161.2	c.-61G>A		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE2A	ENST00000371558.7	c.32G>A	p.Arg11Gln	missense_variant	1/6	1	NM_003336.4	P4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1082021 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 352945

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Syndromic X-linked intellectual disability Nascimento type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L;.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	D;D;.;.
REVEL	Uncertain	0.50
Sift	Benign	0.13	T;T;.;.
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.97	D;.;.;.
Vest4		0.69
MutPred		0.47		Loss of MoRF binding (P = 0.0443);Loss of MoRF binding (P = 0.0443);Loss of MoRF binding (P = 0.0443);Loss of MoRF binding (P = 0.0443);
MVP		0.98
MPC		1.9
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.81
gMVP		0.94

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

Other links and lift over

dbSNP: rs387906728; hg19: chrX-118708706;