rs143447675

chrX-154380897-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000117.3(EMD):c.465C>T(p.Tyr155=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 1,210,507 control chromosomes in the GnomAD database, including 3 homozygotes. There are 245 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., 121 hem., cov: 24)
  • Exomes 𝑓: 0.00042 (1 hom. 124 hem.)
• Consequence: EMD NM_000117.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.31

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-154380897-C-T is Benign according to our data. Variant chrX-154380897-C-T is described in ClinVar as [Benign]. Clinvar id is 42274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154380897-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00371 (417/112464) while in subpopulation AFR AF= 0.0125 (389/31026). AF 95% confidence interval is 0.0115. There are 2 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMD	NM_000117.3	c.465C>T	p.Tyr155=	synonymous_variant	6/6	ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.465C>T	p.Tyr155=	synonymous_variant	6/6	1	NM_000117.3	P1

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 417 AN: 112412 Hom.: 2 Cov.: 24 AF XY: 0.00350 AC XY: 121 AN XY: 34562

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

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: 0.0000377

Gnomad OTH AF: 0.00264

GnomAD3 exomes AF: 0.00112 AC: 205 AN: 183035 Hom.: 0 AF XY: 0.000754 AC XY: 51 AN XY: 67669

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.00117

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: 0.0000612

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000415 AC: 456 AN: 1098043 Hom.: 1 Cov.: 32 AF XY: 0.000341 AC XY: 124 AN XY: 363443

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.00134

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: 0.0000712

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00371 AC: 417 AN: 112464 Hom.: 2 Cov.: 24 AF XY: 0.00349 AC XY: 121 AN XY: 34624

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.00204

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000377

Gnomad4 OTH AF: 0.00260

Alfa AF: 0.00203 Hom.: 11

Bravo AF: 0.00484

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 21, 2012	Tyr155Tyr in exon 06 of EMD: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 1.4% (54/3835) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; rs143447675). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 09, 2018	Variant summary: EMD c.465C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0013 in 87334 control chromosomes, including 69 hemizygotes (gnomAD). To our knowledge, no occurrence of c.465C>T 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 benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2016	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 02, 2015

- -

Emery-Dreifuss muscular dystrophy 1, X-linked Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 21, 2023

- -

X-linked Emery-Dreifuss muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.25
Dann	Benign	0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143447675; hg19: chrX-153609257; COSMIC: COSV100877370; COSMIC: COSV100877370;