X-31223056-C-T

Position:

chrX-31223056-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6BS2_Supporting

The NM_004006.3(DMD):c.9352G>A(p.Ala3118Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000828 in 1,207,202 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 2 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 6.92

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:

DMD (HGNC:):

DMD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP6

Variant X-31223056-C-T is Benign according to our data. Variant chrX-31223056-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 811289.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes 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/exons	MANE	Protein	UniProt
DMD	NM_004006.3 linkuse as main transcript	c.9352G>A	p.Ala3118Thr	missense_variant	64/79	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 linkuse as main transcript	c.9352G>A	p.Ala3118Thr	missense_variant	64/79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112027

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34187

show subpopulations

Gnomad AFR

AF:

0.0000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183500

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67936

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000365

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000639

AC:

AN:

1095175

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

360613

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0000568

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:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000268

AC:

AN:

112027

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34187

show subpopulations

Gnomad4 AFR

AF:

0.0000974

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 09, 2019

The DMD c.9352G>A; p.Ala3118Thr variant (rs200928985), to our knowledge, is not reported in the medical literature but is reported as a variant of uncertain significance in ClinVar (Variation ID: 520520). This variant is found in the Genome Aggregation Database on 2 out of 183,500 alleles, including 1 hemizygote. The alanine at codon 3118 is moderately conserved and computational analyses (SIFT: tolerated, PolyPhen-2: probably damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Ala3118Thr variant is uncertain at this time. -

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

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 10, 2019

- -

DMD-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 04, 2024

The DMD c.9352G>A variant is predicted to result in the amino acid substitution p.Ala3118Thr. This variant has been reported in a cohort of individuals suspected of Duchenne muscular dystrophy or Becker muscular dystrophy; however, detailed clinical information was not available (Kim et al. 2016. PubMed ID: 26743743). This variant is reported in 0.0076% of alleles in individuals of African descent in gnomAD, including one hemizygote in the database. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2024

The p.A3118T variant (also known as c.9352G>A), located in coding exon 64 of the DMD gene, results from a G to A substitution at nucleotide position 9352. The alanine at codon 3118 is replaced by threonine, an amino acid with similar properties. This variant was described in a Duchenne/Becker muscular dystrophy cohort; however, clinical details were not provided (Kim MJ et al. J Mol Diagn, 2016 Mar;18:253-9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the A allele has an overall frequency of 0.0011% (2/183500) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0076% (1/13161) of African/African American alleles. Based on the available evidence, the clinical significance of this variant remains unclear. -

Duchenne muscular dystrophy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;.;T;T;T;.;.;T;.;.;.;T;.;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

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

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.45

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

MetaSVM

Benign

-0.36

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.7

D;N;.;D;D;N;.;N;.;N;D;N;D;D

REVEL

Benign

0.24

Sift

Benign

0.23

T;T;.;T;T;T;.;D;.;D;T;T;T;T

Sift4G

Benign

0.17

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

Polyphen

0.60, 0.98, 0.023, 1.0, 0.058, 1.0

.;.;.;P;D;B;.;D;.;.;.;B;D;.

Vest4

0.70

MVP

0.87

MPC

0.040

ClinPred

0.69

GERP RS

5.2

gMVP

0.36

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