rs727503828

chrX-32365035-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP6 BS2

The NM_004006.3(DMD):c.5010G>T(p.Trp1670Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00042 in 1,208,544 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 136 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. W1670G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., 10 hem., cov: 22)
  • Exomes 𝑓: 0.00043 (0 hom. 126 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 7.79

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 Likely_benign. Variant got -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803
• BP6: Variant X-32365035-C-A is Benign according to our data. Variant chrX-32365035-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166757.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=2}. Variant chrX-32365035-C-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.5010G>T	p.Trp1670Cys	missense_variant	35/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.5010G>T	p.Trp1670Cys	missense_variant	35/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.000307 AC: 34 AN: 110828 Hom.: 0 Cov.: 22 AF XY: 0.000303 AC XY: 10 AN XY: 33040

Gnomad AFR AF: 0.0000656

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: 0.000342

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000566

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000213 AC: 39 AN: 183125 Hom.: 0 AF XY: 0.000133 AC XY: 9 AN XY: 67669

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000250

Gnomad NFE exome AF: 0.000404

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000431 AC: 473 AN: 1097716 Hom.: 0 Cov.: 30 AF XY: 0.000347 AC XY: 126 AN XY: 363202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000395

Gnomad4 NFE exome AF: 0.000523

Gnomad4 OTH exome AF: 0.000326

GnomAD4 genome AF: 0.000307 AC: 34 AN: 110828 Hom.: 0 Cov.: 22 AF XY: 0.000303 AC XY: 10 AN XY: 33040

Gnomad4 AFR AF: 0.0000656

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000342

Gnomad4 NFE AF: 0.000566

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000427 Hom.: 3

Bravo AF: 0.000321

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000655

EpiControl AF: 0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2019	This variant is associated with the following publications: (PMID: 30564623, 14695533) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	DMD: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2024	Variant summary: DMD c.5010G>T (p.Trp1670Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 1208544 control chromosomes, including 136 hemizygotes. The observed variant frequency is approximately 38 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is benign. c.5010G>T has been reported in at-least one gender unspecified individual affected with DMD and a non-informative genotype (example: Hofstra_2004). This report does not provide unequivocal conclusions about association of the variant with Dystrophinopathies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29016797, 14695533). ClinVar contains an entry for this variant (Variation ID: 166757). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2015	The p.Trp1670Cys variant in DMD has been identified in one individual with DMD ( Hofstra 2004). It has also been identified in 23/47847 European chromosomes, inc luding 4 hemizygotes, by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs727503828). Computational prediction tools and conserv ation analysis suggest that this variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. In summary, the cl inical significance of the p.Trp1670Cys variant is uncertain. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2018

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. -

Duchenne muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	26
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.84
MutPred		0.70		.;.;Gain of catalytic residue at L1671 (P = 0.0224);Gain of catalytic residue at L1671 (P = 0.0224);.;
MVP		0.90
MPC		0.10
ClinPred		0.59	D
GERP RS		5.5
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727503828; hg19: chrX-32383152;