rs374981936

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_000117.3(EMD):c.598T>C(p.Trp200Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,210,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W200L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000036 ( 0 hom. 15 hem. )

Consequence

EMD
NM_000117.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.00

Publications

1 publications found

Variant links:

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]

EMD Gene-Disease associations (from GenCC):

X-linked Emery-Dreifuss muscular dystrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
heart conduction disease
Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp

EMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34350592).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000978 (11/112532) while in subpopulation NFE AF = 0.000169 (9/53126). AF 95% confidence interval is 0.0000874. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMD	NM_000117.3 link	c.598T>C	p.Trp200Arg	missense_variant	Exon 6 of 6	ENST00000369842.9	NP_000108.1	P50402

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9 link	c.598T>C	p.Trp200Arg	missense_variant	Exon 6 of 6	1	NM_000117.3	ENSP00000358857.4		P50402

Frequencies

GnomAD3 genomes

AF:

0.0000978

AC:

AN:

112532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000645

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:

0.000169

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

182990

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000364

AC:

AN:

1097993

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

363437

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40297

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000475

AC:

AN:

842121

Other (OTH)

AF:

0.00

AC:

AN:

46089

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000978

AC:

AN:

112532

Hom.:

Cov.:

AF XY:

0.0000865

AC XY:

AN XY:

34682

show subpopulations

African (AFR)

AF:

0.0000645

AC:

AN:

30987

American (AMR)

AF:

0.00

AC:

AN:

10738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3594

South Asian (SAS)

AF:

0.00

AC:

AN:

2741

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6257

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000169

AC:

AN:

53126

Other (OTH)

AF:

0.00

AC:

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked Emery-Dreifuss muscular dystrophy

Uncertain:1Benign:1

Oct 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jul 18, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Trp200Arg variant in EMD has not been previously reported in individuals wit h cardiomyopathy, but has been identified in 2/6728 European American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs374981936). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Trp200Arg variant is uncertain. -

Emery-Dreifuss muscular dystrophy

Uncertain:1

Mar 24, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:1

Feb 22, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

Cardiovascular phenotype

Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.W200R variant (also known as c.598T>C), located in coding exon 6 of the EMD gene, results from a T to C substitution at nucleotide position 598. The tryptophan at codon 200 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the C allele has an overall frequency of 0.002% (5/204696) total alleles studied, with 2 hemizygote(s) observed. The highest observed frequency was 0.005% (5/92220) of European (non-Finnish) alleles. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.58

D;T

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.61

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.6

L;.

PhyloP100

1.0

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.18

T;T

Polyphen

0.97

D;.

Vest4

0.32

MutPred

0.45

Gain of methylation at W200 (P = 0.0267);.;

MVP

0.82

MPC

1.3

ClinPred

0.33

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.67

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over