rs1556235119

chrX-119574712-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_003336.4(UBE2A):c.1A>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: 5.68

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_003336.4 (UBE2A) was described as [Likely_pathogenic] in ClinVar as 520743
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-119574712-A-G is Pathogenic according to our data. Variant chrX-119574712-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520791.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE2A	NM_003336.4	c.1A>G	p.Met1?	start_lost	1/6	ENST00000371558.7
UBE2A	NM_181762.3	c.1A>G	p.Met1?	start_lost	1/5
UBE2A	NM_001282161.2	c.-92A>G		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE2A	ENST00000371558.7	c.1A>G	p.Met1?	start_lost	1/6	1	NM_003336.4	P4

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 15, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;.;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.077	D
MutationTaster	Benign	0.92	N;N
PROVEAN	Uncertain	-3.2	D;D;.;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.92
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.047);Gain of catalytic residue at M1 (P = 0.047);Gain of catalytic residue at M1 (P = 0.047);Gain of catalytic residue at M1 (P = 0.047);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1556235119; hg19: chrX-118708675;