rs727503037

Positions:

• chrX-154381143-C-G
• chrX-154381143-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000369842.9(EMD):​c.711C>G​(p.Ile237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I237V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: EMD ENST00000369842.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.100

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22691578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EMD	NM_000117.3	c.711C>G	p.Ile237Met	missense_variant	6/6	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.711C>G	p.Ile237Met	missense_variant	6/6	1	NM_000117.3	ENSP00000358857	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 12, 2015

The p.Ile237Met variant in EMD has not been previously reported in individuals w ith cardiomyopathy and was absent from large population studies. Computational p rediction tools and conservation analysis suggest that the p.Ile237Met variant m ay not impact the protein, though this information is not predictive enough to r ule out pathogenicity. In summary, the clinical significance of the p.Ile237Met variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Uncertain	0.48	T;T
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.63	N;N
REVEL	Benign	0.26
Sift	Benign	0.069	T;T
Sift4G	Benign	0.061	T;T
Polyphen		0.91	P;.
Vest4		0.28
MutPred		0.32		Loss of helix (P = 0.3949);.;
MVP		0.57
MPC		0.56
ClinPred		0.35	T
GERP RS		3.2
Varity_R		0.097
gMVP		0.27

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: rs727503037; hg19: chrX-153609503;