X-154379486-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000117.3 (EMD) was described as [Pathogenic] in ClinVar as 281087
• 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/exons	MANE	UniProt
EMD	NM_000117.3	c.2T>G	p.Met1?	start_lost	1/6	ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.2T>G	p.Met1?	start_lost	1/6	1	NM_000117.3	P1

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 02, 2020

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 create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of the initiator codon has been observed in individual(s) with Emery-Dreifuss muscular dystrophy (PMID: 9266737, 10382909, 7894480). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the EMD mRNA. The next in-frame methionine is located at codon 73. -

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
MutationTaster	Benign	1.0	D;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;