rs1557182654

chrX-154381012-TCA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000117.3(EMD):c.581_582del(p.Ser194PhefsTer15) variant causes a frameshift 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S194S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EMD NM_000117.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.13

Genes affected

EMD (HGNC:3331): (emerin) Emerin is a serine-rich nuclear membrane protein and a member of the nuclear lamina-associated protein family. It mediates membrane anchorage to the cytoskeleton. Dreifuss-Emery muscular dystrophy is an X-linked inherited degenerative myopathy resulting from mutation in the emerin gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154381012-TCA-T is Pathogenic according to our data. Variant chrX-154381012-TCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 531738.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMD	NM_000117.3	c.581_582del	p.Ser194PhefsTer15	frameshift_variant	6/6	ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.581_582del	p.Ser194PhefsTer15	frameshift_variant	6/6	1	NM_000117.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 29, 2017

A different truncation (p.Trp226*) that lies downstream of this variant has been determined to be pathogenic (PMID: 8589715, 15967842). This suggests that deletion of this region of the EMD protein is causative of disease. This variant has not been reported in the literature in individuals with EMD-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the EMD gene (p.Ser194Phefs*15). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acids of the EMD protein. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1557182654; hg19: chrX-153609372;