rs201140396

chrX-154379677-C-GchrX-154379677-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000117.3(EMD):c.83-13C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000555 in 1,205,852 control chromosomes in the GnomAD database, including 3 homozygotes. There are 180 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., 83 hem., cov: 25)
  • Exomes 𝑓: 0.00032 (2 hom. 97 hem.)
• Consequence: EMD NM_000117.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.467

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-154379677-C-G is Benign according to our data. Variant chrX-154379677-C-G is described in ClinVar as [Benign]. Clinvar id is 42279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154379677-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00282 (318/112686) while in subpopulation AFR AF= 0.00969 (302/31155). AF 95% confidence interval is 0.00879. There are 1 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 82 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMD	NM_000117.3	c.83-13C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.83-13C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000117.3	P1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 316 AN: 112638 Hom.: 1 Cov.: 25 AF XY: 0.00236 AC XY: 82 AN XY: 34800

Gnomad AFR AF: 0.00965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000927

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.000663

GnomAD3 exomes AF: 0.000755 AC: 129 AN: 170813 Hom.: 0 AF XY: 0.000428 AC XY: 27 AN XY: 63147

Gnomad AFR exome AF: 0.00999

Gnomad AMR exome AF: 0.000482

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000135

Gnomad OTH exome AF: 0.000473

GnomAD4 exome AF: 0.000321 AC: 351 AN: 1093166 Hom.: 2 Cov.: 31 AF XY: 0.000270 AC XY: 97 AN XY: 359708

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.000484

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.0000926

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000596

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.00282 AC: 318 AN: 112686 Hom.: 1 Cov.: 25 AF XY: 0.00238 AC XY: 83 AN XY: 34858

Gnomad4 AFR AF: 0.00969

Gnomad4 AMR AF: 0.000925

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00108

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000377

Gnomad4 OTH AF: 0.000655

Alfa AF: 0.000174 Hom.: 1

Bravo AF: 0.00302

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 13, 2020	Variant summary: EMD c.83-13C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 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 0.001 in 192415 control chromosomes, predominantly at a frequency of 0.01 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in EMD causing Cardiomyopathy phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.83-13C>G has been reported in the literature in an individual affected with Dilated Cardiomyopathy (DCM). This report however, does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 21, 2015	c.83-13C>G in intron 1 of EMD: This variant is not expected to have clinical sig nificance because it has been identified in 1% (63/5981) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201140396). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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	-0.79
Cadd	Benign	6.5
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs201140396; hg19: chrX-153608037;