X-119574750-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_003336.4(UBE2A):c.39C>A(p.Phe13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F13F) has been classified as Likely benign.

• 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: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE2A	NM_003336.4	c.39C>A	p.Phe13Leu	missense_variant	1/6	ENST00000371558.7
UBE2A	NM_181762.3	c.39C>A	p.Phe13Leu	missense_variant	1/5
UBE2A	NM_001282161.2	c.-54C>A		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE2A	ENST00000371558.7	c.39C>A	p.Phe13Leu	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: 1081094 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 352312

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability Nascimento type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0109 - This gene is known to be associated with X-linked recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a phenylalanine to a leucine (exon 1). (N) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (ubiquitin-conjugating enzyme domain; PDB, NCBI). (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;.;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.61	N;.;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.7	D;D;.;.
REVEL	Uncertain	0.39
Sift	Benign	0.52	T;T;.;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.53
MutPred		0.50		Loss of methylation at K14 (P = 0.0289);Loss of methylation at K14 (P = 0.0289);Loss of methylation at K14 (P = 0.0289);Loss of methylation at K14 (P = 0.0289);
MVP		0.94
MPC		1.9
ClinPred		0.88	D
GERP RS		4.3
Varity_R		0.73
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-118708713;