X-32468639-C-T

Variant names:

• chrX-32468639-C-T
• rs1800268
• NM_004006.3:c.3021G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004006.3(DMD):​c.3021G>A​(p.Ser1007Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,209,308 control chromosomes in the GnomAD database, including 158 homozygotes. There are 6,864 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (10 hom., 359 hem., cov: 22)
  • Exomes 𝑓: 0.018 (148 hom. 6505 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.0460

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant X-32468639-C-T is Benign according to our data. Variant chrX-32468639-C-T is described in ClinVar as [Benign]. Clinvar id is 94548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32468639-C-T is described in Lovd as [Benign]. Variant chrX-32468639-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.046 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1354/111514) while in subpopulation NFE AF= 0.019 (1010/53048). AF 95% confidence interval is 0.0181. There are 10 homozygotes in gnomad4. There are 359 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.3021G>A	p.Ser1007Ser	synonymous_variant	Exon 23 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.3021G>A	p.Ser1007Ser	synonymous_variant	Exon 23 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1352 AN: 111459 Hom.: 10 Cov.: 22 AF XY: 0.0106 AC XY: 357 AN XY: 33667

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.00227

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00936

Gnomad FIN AF: 0.00183

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0141

GnomAD3 exomes AF: 0.0122 AC: 2235 AN: 182498 Hom.: 12 AF XY: 0.0134 AC XY: 904 AN XY: 67298

Gnomad AFR exome AF: 0.00236

Gnomad AMR exome AF: 0.00947

Gnomad ASJ exome AF: 0.00121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0102

Gnomad FIN exome AF: 0.00288

Gnomad NFE exome AF: 0.0201

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.0182 AC: 19962 AN: 1097794 Hom.: 148 Cov.: 30 AF XY: 0.0179 AC XY: 6505 AN XY: 363266

Gnomad4 AFR exome AF: 0.00284

Gnomad4 AMR exome AF: 0.00975

Gnomad4 ASJ exome AF: 0.00206

Gnomad4 EAS exome AF: 0.0000663

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.00375

Gnomad4 NFE exome AF: 0.0214

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.0121 AC: 1354 AN: 111514 Hom.: 10 Cov.: 22 AF XY: 0.0106 AC XY: 359 AN XY: 33732

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.0171

Gnomad4 ASJ AF: 0.00227

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00939

Gnomad4 FIN AF: 0.00183

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0139

Alfa AF: 0.0140 Hom.: 109

Bravo AF: 0.0125

EpiCase AF: 0.0182

EpiControl AF: 0.0220

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Mar 31, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 18, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DMD c.3021G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 204360 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.02 in the gnomAD database, including 11 homozygotes and 717 hemizygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Duchenne muscular dystrophy phenotype (0.011), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.3021G>A in individuals affected with Duchenne muscular dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Oct 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser1007Ser in exon 23 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 1.7% (112/6728) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/; dbSNP rs1800268). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Oct 26, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Apr 20, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 3B Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Jun 12, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.63
DANN	Benign	0.59

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

Other links and lift over

dbSNP: rs1800268; hg19: chrX-32486756; COSMIC: COSV63750403;