rs373832446

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_004006.3(DMD):c.8255A>G(p.Tyr2752Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,208,631 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 93 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. Y2752H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.00026 ( 0 hom. 88 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.34

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=0.23642498).

BP6

Variant X-31507416-T-C is Benign according to our data. Variant chrX-31507416-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94797.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=2}.

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.8255A>G	p.Tyr2752Cys	missense_variant	56/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.8255A>G	p.Tyr2752Cys	missense_variant	56/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

112350

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34500

show subpopulations

Gnomad AFR

AF:

0.0000647

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000945

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000263

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000168

AC:

AN:

178045

Hom.:

AF XY:

0.0000794

AC XY:

AN XY:

62971

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000369

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000369

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000256

AC:

281

AN:

1096281

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

AN XY:

361749

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000318

Gnomad4 OTH exome

AF:

0.000261

GnomAD4 genome

AF:

0.000151

AC:

AN:

112350

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34500

show subpopulations

Gnomad4 AFR

AF:

0.0000647

Gnomad4 AMR

AF:

0.0000945

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000263

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 26, 2018

The DMD p.Tyr2752Cys variant (rs373832446), to our knowledge, has not been reported in the medical literature or gene specific databases; however, this variant is also listed in the ClinVar database with conflicting interpretations (Variation ID: 94797). This variant is found in the general population with an allele frequency in non-Finnish Europeans of 0.03% (28/87,438 alleles; including 5 hemizygotes) in the Genome Aggregation Database. The tyrosine at codon 2752 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Thus, based on the available information, the clinical significance of this variant is uncertain. -

Duchenne muscular dystrophy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2022

This alteration is classified as likely 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

0.29

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.22

Cadd

Uncertain

Dann

Uncertain

1.0

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

D;.;.;.;.;D;.;D;D;.

M_CAP

Benign

0.058

MetaRNN

Benign

0.24

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.86

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.5

D;.;D;D;D;.;D;.;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0040

D;.;D;D;D;.;D;.;D;D

Sift4G

Uncertain

0.019

D;D;D;D;D;D;D;D;D;D

Polyphen

0.99, 1.0, 0.98, 0.97

.;.;D;D;D;.;D;.;.;D

Vest4

0.77, 0.78, 0.77, 0.79, 0.67, 0.71, 0.77, 0.78

MVP

0.64

MPC

0.10

ClinPred

0.42

GERP RS

4.3

gMVP

0.61

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