X-32485077-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004006.3(DMD):c.2645A>G(p.Asp882Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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. D882V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.68 (18016 hom., 22248 hem., cov: 23)
  • Exomes 𝑓: 0.68 (171444 hom. 248464 hem.)
  • Failed GnomAD Quality Control
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.937

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8961167E-5).
• BP6: Variant X-32485077-T-C is Benign according to our data. Variant chrX-32485077-T-C is described in ClinVar as [Benign]. Clinvar id is 166842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32485077-T-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 18029 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.2645A>G	p.Asp882Gly	missense_variant	21/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.2645A>G	p.Asp882Gly	missense_variant	21/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.679 AC: 74818 AN: 110201 Hom.: 18029 Cov.: 23 AF XY: 0.684 AC XY: 22212 AN XY: 32453

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.687

GnomAD3 exomes AF: 0.728 AC: 133392 AN: 183171 Hom.: 31450 AF XY: 0.724 AC XY: 48969 AN XY: 67641

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.854

Gnomad ASJ exome AF: 0.610

Gnomad EAS exome AF: 0.886

Gnomad SAS exome AF: 0.780

Gnomad FIN exome AF: 0.812

Gnomad NFE exome AF: 0.660

Gnomad OTH exome AF: 0.699

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.682 AC: 748068 AN: 1097332 Hom.: 171444 Cov.: 39 AF XY: 0.684 AC XY: 248464 AN XY: 363044

Gnomad4 AFR exome AF: 0.626

Gnomad4 AMR exome AF: 0.844

Gnomad4 ASJ exome AF: 0.616

Gnomad4 EAS exome AF: 0.854

Gnomad4 SAS exome AF: 0.780

Gnomad4 FIN exome AF: 0.805

Gnomad4 NFE exome AF: 0.659

Gnomad4 OTH exome AF: 0.686

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.679 AC: 74834 AN: 110252 Hom.: 18016 Cov.: 23 AF XY: 0.684 AC XY: 22248 AN XY: 32514

Gnomad4 AFR AF: 0.630

Gnomad4 AMR AF: 0.765

Gnomad4 ASJ AF: 0.615

Gnomad4 EAS AF: 0.875

Gnomad4 SAS AF: 0.789

Gnomad4 FIN AF: 0.813

Gnomad4 NFE AF: 0.661

Gnomad4 OTH AF: 0.679

Alfa AF: 0.661 Hom.: 85314

Bravo AF: 0.679

TwinsUK AF: 0.664 AC: 2463

ALSPAC AF: 0.652 AC: 1883

ESP6500AA AF: 0.628 AC: 2407

ESP6500EA AF: 0.663 AC: 4460

ExAC AF: 0.719 AC: 87334

EpiCase AF: 0.659

EpiControl AF: 0.654

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	This is a RefSeq error. The reference base (c.2645A) is the minor allele. This a llele (A) has been identified in 34% (2268/6728) of European American chromosome s and 37% (1426/3833) of African American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs228406) and thus meets c riteria to be classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2019	This variant is associated with the following publications: (PMID: 30342905, 29604111) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Duchenne muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 20, 2017

- -

Dilated cardiomyopathy 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.90
Cadd	Benign	15
Dann	Benign	0.80
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.015	T;.;T;T
MetaRNN	Benign	0.000019	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.056
MPC		0.016
ClinPred		0.0016	T
GERP RS		3.1
gMVP		0.14

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: rs228406; hg19: chrX-32503194; COSMIC: COSV63760235;