X-154381143-C-G

Variant names:

• chrX-154381143-C-G
• rs727503037
• NM_000117.3:c.711C>G

Variant summary

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

The NM_000117.3(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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: EMD NM_000117.3 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 rank	MANE	Protein	UniProt
EMD	NM_000117.3	c.711C>G	p.Ile237Met	missense_variant	Exon 6 of 6	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.711C>G	p.Ile237Met	missense_variant	Exon 6 of 6	1	NM_000117.3	ENSP00000358857.4

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

Oct 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
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;