rs16990264

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004006.3(DMD):c.5016T>A(p.Asn1672Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,208,793 control chromosomes in the GnomAD database, including 95 homozygotes. There are 1,291 hemizygotes in GnomAD. In-silico tool predicts 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. N1672T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 54 hom., 576 hem., cov: 22)

Exomes 𝑓: 0.0023 ( 41 hom. 715 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.179

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073643923).

BP6

Variant X-32365029-A-T is Benign according to our data. Variant chrX-32365029-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 94648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32365029-A-T is described in Lovd as [Benign]. Variant chrX-32365029-A-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.5016T>A	p.Asn1672Lys	missense_variant	35/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.5016T>A	p.Asn1672Lys	missense_variant	35/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

2165

AN:

110989

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

566

AN XY:

33169

show subpopulations

Gnomad AFR

AF:

0.0655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0110

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00226

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.000415

Gnomad OTH

AF:

0.0161

GnomAD3 exomes

AF:

0.00610

AC:

1117

AN:

183125

Hom.:

AF XY:

0.00446

AC XY:

302

AN XY:

67667

show subpopulations

Gnomad AFR exome

AF:

0.0710

Gnomad AMR exome

AF:

0.00467

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000891

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00228

AC:

2506

AN:

1097753

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

715

AN XY:

363243

show subpopulations

Gnomad4 AFR exome

AF:

0.0683

Gnomad4 AMR exome

AF:

0.00546

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00102

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000233

Gnomad4 OTH exome

AF:

0.00530

GnomAD4 genome

AF:

0.0196

AC:

2179

AN:

111040

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

576

AN XY:

33230

show subpopulations

Gnomad4 AFR

AF:

0.0659

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00189

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000415

Gnomad4 OTH

AF:

0.0159

Alfa

AF:

0.00325

Hom.:

Bravo

AF:

0.0225

ESP6500AA

AF:

0.0673

AC:

258

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.00685

AC:

831

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 20, 2015	p.Asn1672Lys in exon 35 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 7.2% (760/10546) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs16990261). -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 23, 2021	- -

Dilated cardiomyopathy 3B

Benign:2

Likely benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Benign, for Cardiomyopathy, dilated, 3B, in X-linked Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2-Supporting => BS2 downgraded in strength to supporting. -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2018	This variant is associated with the following publications: (PMID: 27896284, 23299917, 12354438, 27884173) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	- -

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

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 21, 2017

- -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2016

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. -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.68

Cadd

Benign

Dann

Uncertain

0.98

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.82

T;.;T;T;T

MetaRNN

Benign

0.0074

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0e-37

P;P

PrimateAI

Uncertain

0.50

Sift4G

Benign

0.25

T;T;T;T;D

Polyphen

0.25

.;B;.;.;.

Vest4

0.22

MutPred

0.65

.;.;Gain of ubiquitination at N1672 (P = 0.017);Gain of ubiquitination at N1672 (P = 0.017);.;

MVP

0.66

MPC

0.056

ClinPred

0.027

GERP RS

-0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over