X-119574743-G-A

Variant names:

• chrX-119574743-G-A
• rs387906728
• NM_003336.4:c.32G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 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
• Publications: 11 publications found

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]

UBE2A Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability Nascimento type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

LOC124905208 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a chain Ubiquitin-conjugating enzyme E2 A (size 151) in uniprot entity UBE2A_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_003336.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.4624 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to syndromic X-linked intellectual disability Nascimento type.
• 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 rank	MANE	Protein	UniProt
UBE2A	NM_003336.4	c.32G>A	p.Arg11Gln	missense_variant	Exon 1 of 6	ENST00000371558.7	NP_003327.2
UBE2A	NM_181762.3	c.32G>A	p.Arg11Gln	missense_variant	Exon 1 of 5		NP_861427.1
UBE2A	NM_001282161.2	c.-61G>A		5_prime_UTR_variant	Exon 1 of 6		NP_001269090.1
LOC124905208	XR_007068307.1	n.-248C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE2A	ENST00000371558.7	c.32G>A	p.Arg11Gln	missense_variant	Exon 1 of 6	1	NM_003336.4	ENSP00000360613.2

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

African (AFR) AF: 0.00 AC: 0 AN: 26137

American (AMR) AF: 0.00 AC: 0 AN: 33435

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18981

East Asian (EAS) AF: 0.00 AC: 0 AN: 29416

South Asian (SAS) AF: 0.00 AC: 0 AN: 51702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37859

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4077

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 834963

Other (OTH) AF: 0.00 AC: 0 AN: 45451

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

Jun 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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;.
PhyloP100		6.2
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
PromoterAI		0.0098	Neutral
Varity_R		0.81
gMVP		0.94
Mutation Taster		=18/82	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906728; hg19: chrX-118708706;