rs1556244406

Variant names:

• chrX-119583167-GC-G
• rs1556244406
• NM_003336.4:c.373delC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_003336.4(UBE2A):​c.373delC​(p.Gln125ArgfsTer20) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: UBE2A NM_003336.4 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.98
• Publications: 0 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, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-119583167-GC-G is Pathogenic according to our data. Variant chrX-119583167-GC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 559652.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003336.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE2A	NM_003336.4	MANE Select	c.373delC	p.Gln125ArgfsTer20	frameshift	Exon 6 of 6	NP_003327.2
	UBE2A	NM_181762.3		c.283delC	p.Gln95ArgfsTer20	frameshift	Exon 5 of 5	NP_861427.1	P49459-2
	UBE2A	NM_001282161.2		c.274delC	p.Gln92ArgfsTer20	frameshift	Exon 6 of 6	NP_001269090.1	A0A0D9SG71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE2A	ENST00000371558.7	TSL:1 MANE Select	c.373delC	p.Gln125ArgfsTer20	frameshift	Exon 6 of 6	ENSP00000360613.2	P49459-1
	UBE2A	ENST00000371569.6	TSL:1	n.1394delC		non_coding_transcript_exon	Exon 3 of 3
	UBE2A	ENST00000696533.1		c.589delC	p.Gln197ArgfsTer20	frameshift	Exon 8 of 8	ENSP00000512694.1	A0A8Q3SIL6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Syndromic X-linked intellectual disability Nascimento type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0

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: rs1556244406; hg19: chrX-118717130;