X-154379486-T-G

Variant names:

• chrX-154379486-T-G
• NM_000117.3:c.2T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000117.3(EMD):​c.2T>G​(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 26)
• Consequence: EMD NM_000117.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.377

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 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 73 codons. Genomic position: 154379971. Lost 0.284 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154379486-T-G is Pathogenic according to our data. Variant chrX-154379486-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 1074958.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-154379486-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMD	NM_000117.3	c.2T>G	p.Met1?	start_lost	Exon 1 of 6	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.2T>G	p.Met1?	start_lost	Exon 1 of 6	1	NM_000117.3	ENSP00000358857.4

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 26

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy Pathogenic:1

Oct 02, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the EMD mRNA. The next in-frame methionine is located at codon 73. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator codon has been observed in individual(s) with Emery-Dreifuss muscular dystrophy (PMID: 9266737, 10382909, 7894480). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Uncertain	0.73	D;T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.61	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.99	D;.
Vest4		0.67
MutPred		0.62		Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);
MVP		1.0
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-153607846;