chrX-31203964-T-C

Position:

• chrX-31203964-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):​c.9804A>G​(p.Gln3268=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,204,139 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 9 hem., cov: 24)
  • Exomes 𝑓: 0.000088 (0 hom. 31 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.200

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant X-31203964-T-C is Benign according to our data. Variant chrX-31203964-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31203964-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000879 (96/1091871) while in subpopulation EAS AF= 0.00239 (72/30176). AF 95% confidence interval is 0.00194. There are 0 homozygotes in gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.9804A>G	p.Gln3268=	synonymous_variant	67/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.9804A>G	p.Gln3268=	synonymous_variant	67/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.000249 AC: 28 AN: 112268 Hom.: 0 Cov.: 24 AF XY: 0.000261 AC XY: 9 AN XY: 34428

Gnomad AFR AF: 0.000811

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000558

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000657

GnomAD3 exomes AF: 0.000300 AC: 55 AN: 183250 Hom.: 0 AF XY: 0.000266 AC XY: 18 AN XY: 67720

Gnomad AFR exome AF: 0.000684

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00304

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000879 AC: 96 AN: 1091871 Hom.: 0 Cov.: 29 AF XY: 0.0000867 AC XY: 31 AN XY: 357465

Gnomad4 AFR exome AF: 0.000495

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00239

Gnomad4 SAS exome AF: 0.0000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000239

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome AF: 0.000249 AC: 28 AN: 112268 Hom.: 0 Cov.: 24 AF XY: 0.000261 AC XY: 9 AN XY: 34428

Gnomad4 AFR AF: 0.000811

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000558

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000657

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000291

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 14, 2015

- -

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

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

May 20, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 14, 2020

- -

Duchenne muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

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
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.8
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -23

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

Publications

LitVar

Other links and lift over

dbSNP: rs12690372; hg19: chrX-31222081;