rs1557182670

chrX-154381051-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000117.3(EMD):c.621del(p.Pro208LeufsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000887 in 112,784 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R207R) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
• Consequence: EMD NM_000117.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.46

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 Pathogenic. Variant got 14 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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154381051-CG-C is Pathogenic according to our data. Variant chrX-154381051-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 433171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154381051-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMD	NM_000117.3	c.621del	p.Pro208LeufsTer29	frameshift_variant	6/6	ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.621del	p.Pro208LeufsTer29	frameshift_variant	6/6	1	NM_000117.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000887 AC: 1 AN: 112784 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34912

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000887 AC: 1 AN: 112784 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34912

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Jul 19, 2016

- -

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 06, 2018

This sequence change results in a premature translational stop signal in the EMD gene (p.Pro208Leufs*29). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acids of the EMD protein. For these reasons, this variant has been classified as Pathogenic. 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 been reported to segregate with Emery-Dreifuss muscular dystrophy in a large extended family (PMID:8595407, 9195226). This variant is also known as "delG at nucleotide position 1679" in the literature. ClinVar contains an entry for this variant (Variation ID: 433171). This variant is not present in population databases (ExAC no frequency). -

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: rs1557182670; hg19: chrX-153609411;