rs144594695

chrX-154380898-G-AchrX-154380898-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000117.3(EMD):c.466G>A(p.Gly156Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000155 in 1,210,355 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 50 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G156R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., 29 hem., cov: 24)
  • Exomes 𝑓: 0.000084 (0 hom. 21 hem.)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.919

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 Benign. Variant got -16 ACMG points.

• BP6: Variant X-154380898-G-A is Benign according to our data. Variant chrX-154380898-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 201771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154380898-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000855 (96/112328) while in subpopulation AFR AF= 0.00304 (94/30965). AF 95% confidence interval is 0.00254. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 29 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMD	NM_000117.3	c.466G>A	p.Gly156Ser	missense_variant	6/6	ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.466G>A	p.Gly156Ser	missense_variant	6/6	1	NM_000117.3	P1

Frequencies

GnomAD3 genomes AF: 0.000855 AC: 96 AN: 112278 Hom.: 0 Cov.: 24 AF XY: 0.000842 AC XY: 29 AN XY: 34440

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.000661

GnomAD3 exomes AF: 0.000279 AC: 51 AN: 183014 Hom.: 0 AF XY: 0.000163 AC XY: 11 AN XY: 67650

Gnomad AFR exome AF: 0.00350

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000838 AC: 92 AN: 1098027 Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 21 AN XY: 363425

Gnomad4 AFR exome AF: 0.00265

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.000855 AC: 96 AN: 112328 Hom.: 0 Cov.: 24 AF XY: 0.000841 AC XY: 29 AN XY: 34500

Gnomad4 AFR AF: 0.00304

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.000653

Alfa AF: 0.0000443 Hom.: 2

Bravo AF: 0.000997

ESP6500AA AF: 0.00391 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 19, 2018	Variant summary: EMD c.466G>A (p.Gly156Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 199875 control chromosomes, including 20 hemizygotes, in the gnomAD database. The variant was predominantly observed within the African subpopulation, at a frequency of 0.0032 (including 18 hemizygotes), and although this frequency is somewhat lower than expected for a pathogenic variant in EMD causing Cardiomyopathy (0.0032 vs 0.0071), the large number of hemizygotes among the controls suggests that the variant still might be a benign polymorphism. To our knowledge, no occurrence of c.466G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Emery-Dreifuss muscular dystrophy Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 13, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 26, 2020

- -

X-linked Emery-Dreifuss muscular dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;T
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.0094	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.060	N;N
REVEL	Benign	0.17
Sift	Benign	0.16	T;D
Sift4G	Benign	0.47	T;T
Polyphen		0.67	P;.
Vest4		0.24
MVP		0.59
MPC		0.67
ClinPred		0.012	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.048
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		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: rs144594695; hg19: chrX-153609258;