rs750033728

Variant names:

• chrX-32287714-A-C
• rs750033728
• NM_004006.3:c.6118-13T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_004006.3(DMD):​c.6118-13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,138,140 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000029 (0 hom. 6 hem.)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.34
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-32287714-A-C is Benign according to our data. Variant chrX-32287714-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228593.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High AC in GnomAd4 at 5 XL,AD gene. Variant has AC 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 rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.6118-13T>G		intron_variant	Intron 42 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.6118-13T>G		intron_variant	Intron 42 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.0000455 AC: 5 AN: 109875 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000664

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: 0.0000378

Gnomad OTH AF: 0.000676

GnomAD2 exomes AF: 0.0000224 AC: 3 AN: 134107 AF XY: 0.00

Gnomad AFR exome AF: 0.000108

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000292 AC: 30 AN: 1028225 Hom.: 0 Cov.: 23 AF XY: 0.0000192 AC XY: 6 AN XY: 312819

African (AFR) AF: 0.0000418 AC: 1 AN: 23952

American (AMR) AF: 0.0000311 AC: 1 AN: 32108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18615

East Asian (EAS) AF: 0.00 AC: 0 AN: 27429

South Asian (SAS) AF: 0.00 AC: 0 AN: 47798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3833

European-Non Finnish (NFE) AF: 0.0000328 AC: 26 AN: 793129

Other (OTH) AF: 0.0000462 AC: 2 AN: 43329

GnomAD4 genome AF: 0.0000455 AC: 5 AN: 109915 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32183

African (AFR) AF: 0.0000663 AC: 2 AN: 30160

American (AMR) AF: 0.00 AC: 0 AN: 10145

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2629

East Asian (EAS) AF: 0.00 AC: 0 AN: 3461

South Asian (SAS) AF: 0.00 AC: 0 AN: 2529

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5691

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52902

Other (OTH) AF: 0.000668 AC: 1 AN: 1497

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Aug 19, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6118-13T>G variant in DMD has not been previously reported in individuals with cardiomyopathy. Data from large population studies is insufficient to asses s the frequency of this variant but the variant has been identified in 1/160 of European chromosomes by the 1000 Genomes Project (dbSNP rs750033728). This varia nt is located in the 3' splice region. Computational tools do not suggest an imp act to splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the c.6118-13T>G variant is uncertain. -

Duchenne muscular dystrophy Benign:1

Apr 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.84
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		1.3

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

Other links and lift over

dbSNP: rs750033728; hg19: chrX-32305831;