rs146384458

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_004006.3(DMD):c.3082C>T(p.Arg1028Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000422 in 1,208,686 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1028H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.000036 ( 0 hom. 16 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 4.05

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14430127).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000108 (12/111490) while in subpopulation SAS AF= 0.00225 (6/2671). AF 95% confidence interval is 0.000978. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.3082C>T	p.Arg1028Cys	missense_variant	23/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.3082C>T	p.Arg1028Cys	missense_variant	23/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000108

AC:

AN:

111441

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

33637

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00224

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000385

AC:

AN:

181642

Hom.:

AF XY:

0.0000601

AC XY:

AN XY:

66508

show subpopulations

Gnomad AFR exome

AF:

0.000229

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000159

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.0000355

AC:

AN:

1097196

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

362752

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000995

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.0000869

GnomAD4 genome

AF:

0.000108

AC:

AN:

111490

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

33696

show subpopulations

Gnomad4 AFR

AF:

0.000195

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00225

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.000783

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 11, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Arg1028Cys va riant in DMD has not been previously reported in individuals with cardiomyopathy , but has been identified in 2/8092 African chromosomes (including 1 hemizygous male) and in 1/8681 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs146384458). Arginine (Arg) at pos ition 1028 is not conserved in evolution, and 2 species (tenrec and green sea tu rtle) carry a cysteine (Cys), raising the possibility that this change may be to lerated. In summary, while the clinical significance of the p.Arg1028Cys variant is uncertain, these data suggest that it is more likely to be benign. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 14, 2017

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2021

The p.R1028C variant (also known as c.3082C>T), located in coding exon 23 of the DMD gene, results from a C to T substitution at nucleotide position 3082. The arginine at codon 1028 is replaced by cysteine, an amino acid with highly dissimilar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.004% (8/203475) total alleles studied, with 4 hemizygotes observed. The highest observed frequency was 0.02% (4/18977) of African alleles. This amino acid position is well conserved in available vertebrate species; however, cysteine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Duchenne muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

Cadd

Benign

Dann

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;.;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.67

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.39

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

0.99

.;D;.;.

Vest4

0.34

MVP

0.70

MPC

0.017

ClinPred

0.21

GERP RS

4.2

gMVP

0.33

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