rs1800278

chrX-31478309-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004006.3(DMD):c.8734A>G(p.Asn2912Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,209,467 control chromosomes in the GnomAD database, including 198 homozygotes. There are 5,390 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2912S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (85 hom., 880 hem., cov: 23)
  • Exomes 𝑓: 0.013 (113 hom. 4510 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16
• Conservation: PhyloP100: 0.521

Genes affected

DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015425086).
• BP6: Variant X-31478309-T-C is Benign according to our data. Variant chrX-31478309-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 11268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31478309-T-C is described in Lovd as [Benign]. Variant chrX-31478309-T-C is described in Lovd as [Likely_benign]. Variant chrX-31478309-T-C is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.8734A>G	p.Asn2912Asp	missense_variant	59/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.8734A>G	p.Asn2912Asp	missense_variant	59/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 3178 AN: 111262 Hom.: 85 Cov.: 23 AF XY: 0.0262 AC XY: 875 AN XY: 33438

Gnomad AFR AF: 0.0700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.0434

Gnomad SAS AF: 0.00842

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.00956

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0213 AC: 3896 AN: 183245 Hom.: 51 AF XY: 0.0179 AC XY: 1214 AN XY: 67719

Gnomad AFR exome AF: 0.0767

Gnomad AMR exome AF: 0.0246

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.0458

Gnomad SAS exome AF: 0.0125

Gnomad FIN exome AF: 0.0194

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0133 AC: 14646 AN: 1098149 Hom.: 113 Cov.: 34 AF XY: 0.0124 AC XY: 4510 AN XY: 363505

Gnomad4 AFR exome AF: 0.0722

Gnomad4 AMR exome AF: 0.0245

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.0422

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.0186

Gnomad4 NFE exome AF: 0.00951

Gnomad4 OTH exome AF: 0.0176

GnomAD4 genome AF: 0.0286 AC: 3183 AN: 111318 Hom.: 85 Cov.: 23 AF XY: 0.0263 AC XY: 880 AN XY: 33504

Gnomad4 AFR AF: 0.0700

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.0185

Gnomad4 EAS AF: 0.0433

Gnomad4 SAS AF: 0.00845

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.00956

Gnomad4 OTH AF: 0.0225

Alfa AF: 0.0151 Hom.: 857

Bravo AF: 0.0327

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00831 AC: 24

ESP6500AA AF: 0.0720 AC: 276

ESP6500EA AF: 0.00847 AC: 57

ExAC AF: 0.0211 AC: 2561

EpiCase AF: 0.00840

EpiControl AF: 0.00741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2015	p.Asn2912Asp in exon 59 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 7.6% (802/10506) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs1800278). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2019	Variant summary: DMD c.8734A>G (p.Asn2912Asp) results in a conservative amino acid change located in in a spectrin/alpha-actinin repeat (IPR018159) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.022 in 200085 control chromosomes in the gnomAD database, including 59 homozygotes and 1416 hemizygotes. The observed variant frequency is significantly higher than expected for a pathogenic variant in DMD causing Dystrophinopathies phenotype, strongly suggesting that the variant is benign. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (6x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2014	- -

Duchenne muscular dystrophy Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Sep 01, 1994	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 11, 2017	- -

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 02, 2019

- -

Dilated cardiomyopathy 3B Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 23, 2015

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	0.11
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	15
Dann	Uncertain	0.98
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.61	T;.;.;.;.;T;.;T;T;.
MetaRNN	Benign	0.0015	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N;.;N;N;N;.;N;.;N;N
REVEL	Benign	0.062
Sift	Benign	0.17	T;.;D;T;D;.;T;.;T;D
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T;T
Polyphen		0.019, 0.26, 0.0070, 0.0	.;.;B;B;B;.;B;.;.;B
Vest4		0.12, 0.12, 0.092, 0.072, 0.088, 0.087, 0.073, 0.053, 0.10
MPC		0.044
ClinPred		0.018	T
GERP RS		1.7
gMVP		0.16

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: rs1800278; hg19: chrX-31496426; COSMIC: COSV104414665; COSMIC: COSV104414665;