rs1800267

chrX-32565825-G-AchrX-32565825-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004006.3(DMD):c.1869C>T(p.Leu623=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00615 in 1,209,407 control chromosomes in the GnomAD database, including 282 homozygotes. There are 1,923 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L623L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (125 hom., 928 hem., cov: 23)
  • Exomes 𝑓: 0.0035 (157 hom. 995 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.630

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-32565825-G-A is Benign according to our data. Variant chrX-32565825-G-A is described in ClinVar as [Benign]. Clinvar id is 94482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32565825-G-A is described in Lovd as [Benign]. Variant chrX-32565825-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.1869C>T	p.Leu623=	synonymous_variant	16/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.1869C>T	p.Leu623=	synonymous_variant	16/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 3590 AN: 111694 Hom.: 125 Cov.: 23 AF XY: 0.0274 AC XY: 929 AN XY: 33896

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000734

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000320

Gnomad OTH AF: 0.0293

GnomAD3 exomes AF: 0.00914 AC: 1674 AN: 183164 Hom.: 73 AF XY: 0.00573 AC XY: 388 AN XY: 67712

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000269

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00351 AC: 3848 AN: 1097659 Hom.: 157 Cov.: 30 AF XY: 0.00274 AC XY: 995 AN XY: 363055

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.00591

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000573

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.00825

GnomAD4 genome AF: 0.0321 AC: 3588 AN: 111748 Hom.: 125 Cov.: 23 AF XY: 0.0273 AC XY: 928 AN XY: 33960

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000368

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000320

Gnomad4 OTH AF: 0.0290

Alfa AF: 0.0127 Hom.: 64

Bravo AF: 0.0373

EpiCase AF: 0.000327

EpiControl AF: 0.000712

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Leu623Leu in exon 16 of DMD: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 10.9% (418/3833) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS/; dbSNP rs1800267). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2018	Variant summary: DMD c.1869C>T 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 0.011 in 200065 control chromosomes, predominantly at a frequency of 0.11 within the African subpopulation in the gnomAD database, including 93 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 9.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophiopathies phenotype (0.011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.1869C>T in individuals affected with Dystrophiopathies and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 09, 2017	- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 21, 2017

- -

Dilated cardiomyopathy 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2015

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	4.3
Dann	Benign	0.73

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: rs1800267; hg19: chrX-32583942;