X-31731346-G-C

Variant names:

• chrX-31731346-G-C
• rs10521977
• NM_004006.3:c.7543-1598C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_004006.3(DMD):​c.7543-1598C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 110,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.00011 (0 hom., 3 hem., cov: 23)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 1 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High AC in GnomAd4 at 12 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.7543-1598C>G		intron_variant	Intron 51 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.7543-1598C>G		intron_variant	Intron 51 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.000109 AC: 12 AN: 110525 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000763

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000190

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000109 AC: 12 AN: 110525 Hom.: 0 Cov.: 23 AF XY: 0.0000915 AC XY: 3 AN XY: 32803

African (AFR) AF: 0.00 AC: 0 AN: 30396

American (AMR) AF: 0.00 AC: 0 AN: 10418

Ashkenazi Jewish (ASJ) AF: 0.000763 AC: 2 AN: 2621

East Asian (EAS) AF: 0.00 AC: 0 AN: 3513

South Asian (SAS) AF: 0.00 AC: 0 AN: 2690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5861

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 231

European-Non Finnish (NFE) AF: 0.000190 AC: 10 AN: 52641

Other (OTH) AF: 0.00 AC: 0 AN: 1478

Alfa AF: 0.00 Hom.: 2096

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.3
DANN	Benign	0.41
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

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: rs10521977; hg19: chrX-31749463;