rs794729010

Positions:

• chrX-154379795-G-A
• chrX-154379795-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_Strong PM2 PP3_Strong PP5_Very_Strong

The NM_000117.3(EMD):​c.187+1G>A variant causes a splice donor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 25)
• Consequence: EMD NM_000117.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.82

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 18 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.13594772 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-154379795-G-A is Pathogenic according to our data. Variant chrX-154379795-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1330855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154379795-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMD	NM_000117.3	c.187+1G>A		splice_donor_variant		ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.187+1G>A		splice_donor_variant		1	NM_000117.3	P1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 03, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1330855). This variant is also known as 421G>A. Disruption of this splice site has been observed in individuals with Emery-Dreifuss muscular dystrophy (PMID: 10382909, 19997654). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the EMD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EMD are known to be pathogenic (PMID: 24365856). -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2021	The EMD c.187+1G>A variant is reported in the literature in multiple patients affected with Emery-Dreifuss muscular dystrophy (Deymeer 1993, Yates 1999, Steckiewicz 2016). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 2, which is likely to negatively impact gene function. Additionally, a different variant at this splice donor site (c.187+1G>T) has been reported as pathogenic in ClinVar (variation ID: 201772). Based on available information, this variant is considered to be pathogenic. References: Deymeer F et al. Emery-Dreifuss muscular dystrophy with unusual features. Muscle Nerve. 1993 Dec;16(12):1359-65. PMID: 8232393 Yates JR et al. Genotype-phenotype analysis in X-linked Emery-Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype Neuromuscul Disord. 1999 May;9(3):159-65. PMID: 10382909 Steckiewicz R et al. Cardiac pacing in 21 patients with Emery-Dreifuss muscular dystrophy: a single-centre study with a 39-year follow-up. Kardiol Pol. 2016;74(6):576-83. PMID: 26575312 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	29
DANN	Benign	0.90
FATHMM_MKL	Benign	0.68	D
MutationTaster	Benign	1.0	D;D
GERP RS		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: -1

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-153608155;