rs886044628

Variant names:

• chrX-31146333-T-C
• rs886044628
• NM_004006.3:c.10879A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_004006.3(DMD):​c.10879A>G​(p.Met3627Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,096,924 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3627K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.27
• Publications: 0 publications found

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]

DMD Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000297249 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18075418).
• BS2: High AC in GnomAdExome4 at 5 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.10879A>G	p.Met3627Val	missense_variant	Exon 76 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.10879A>G	p.Met3627Val	missense_variant	Exon 76 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096924 Hom.: 0 Cov.: 30 AF XY: 0.00000828 AC XY: 3 AN XY: 362466

African (AFR) AF: 0.0000379 AC: 1 AN: 26368

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30180

South Asian (SAS) AF: 0.00 AC: 0 AN: 54109

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.000262 AC: 1 AN: 3814

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841324

Other (OTH) AF: 0.0000435 AC: 2 AN: 46025

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Aug 29, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 08, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Uncertain:1

Aug 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3627 of the DMD protein (p.Met3627Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 291040). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.24	.;.;T;T;T;.;.;T;.;.;.;T;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D;.;.;.;.;D;.;D;D;D;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		3.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.67	N;N;.;N;N;N;.;N;.;N;N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.34	T;T;.;T;T;T;.;D;.;D;T;T;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.017, 0.0010, 0.073	.;.;.;B;B;B;.;B;.;.;.;B;B;.
Vest4		0.25
MutPred		0.17		.;.;.;.;.;.;.;.;.;Loss of loop (P = 0.1242);.;.;.;.;
MVP		0.73
MPC		0.017
ClinPred		0.63	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.23
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886044628; hg19: chrX-31164450; COSMIC: COSV100629006;