dbSNP rs1556235129: UBE2A:p.Met1? (chrX-119574713-T-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_003336.4(UBE2A):c.2T>G(p.Met1?) variant causes a start lost 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 Likely pathogenic (★).

Frequency

Genomes: not found (cov: 24)

Consequence

UBE2A
NM_003336.4 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.74

Publications

0 publications found

Variant links:

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)

UBE2A links:

LOC124905208 (HGNC:):

LOC124905208 links:

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ACMG classification

Classification was made for transcript

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

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 10 codons. Genomic position: 119574739. Lost 0.061 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant X-119574713-T-G is Pathogenic according to our data. Variant chrX-119574713-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 520743.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
UBE2A	NM_003336.4 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 6	ENST00000371558.7	NP_003327.2
UBE2A	NM_181762.3 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 5		NP_861427.1
UBE2A	NM_001282161.2 link	c.-91T>G		5_prime_UTR_variant	Exon 1 of 6		NP_001269090.1
LOC124905208	XR_007068307.1 link	n.-218A>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE2A	ENST00000371558.7 link	c.2T>G	p.Met1?	start_lost	Exon 1 of 6	1	NM_003336.4	ENSP00000360613.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Aug 14, 2015

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.67

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.59

D;.;.;T

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.095

PhyloP100

4.7

PROVEAN

Pathogenic

-4.5

D;D;.;.

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.91

MutPred

0.97

Gain of methylation at M1 (P = 0.0101);Gain of methylation at M1 (P = 0.0101);Gain of methylation at M1 (P = 0.0101);Gain of methylation at M1 (P = 0.0101);

MVP

0.96

ClinPred

1.0

GERP RS

5.2

PromoterAI

-0.34

Neutral

(source)

Varity_R

0.97

gMVP

0.98

Mutation Taster

=18/182

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over