rs1556235129

Variant names:

• chrX-119574713-T-G
• rs1556235129
• NM_003336.4:c.2T>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Supporting PM2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.74

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]

LOC124905208 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. 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 id is 520743.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D;.;.;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.095	D
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	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.98

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: rs1556235129; hg19: chrX-118708676;