rs727503036

Positions:

• chrX-154380232-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000117.3(EMD):​c.266-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. 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: 24)
• Consequence: EMD NM_000117.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.37

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]

EMD (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 11, offset of -1, new splice context is: accgctgccccccttcccAGggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154380232-A-G is Pathogenic according to our data. Variant chrX-154380232-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 163403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154380232-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMD	NM_000117.3	c.266-2A>G		splice_acceptor_variant, intron_variant		ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.266-2A>G		splice_acceptor_variant, intron_variant		1	NM_000117.3	ENSP00000358857.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8595407, 10428430, 1178008, 1998333, 21697856, 7294729, 10382909) -

Neuromuscular disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 24, 2010

- -

Emery-Dreifuss muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 16, 2020

Variant summary: EMD c.266-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 acceptor site. Four predict the variant creates a 3 acceptor site. Consistent with these predictions, several publications report that this variant affects normal splicing (e.g. Bione_1995, Nevo_1999). In addition, Nevo et al report that the splicing site was shifted back one base pair (bp), which resulted in a one bp insertion shifting of the reading frame and a stop codon after three amino acids (Nevo_1999). The variant was absent in 181283 control chromosomes (gnomAD). c.266-2A>G has been reported in the literature in individuals affected with Emery-Dreifuss Muscular Dystrophy (Bione_1995, Brown_2011, Nevo_1999). These data indicate that the variant is likely to be associated with disease. Nevo et al report absence of Emerin staining in patient samples carrying the variant (Nevo_1999). One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	34
DANN	Benign	0.96
FATHMM_MKL	Benign	0.36	N
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 1
DS_AL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727503036; hg19: chrX-153608592;