rs1241760732

Variant names:

• chrX-32310253-C-T
• rs1241760732
• NM_004006.3:c.5946G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_004006.3(DMD):​c.5946G>A​(p.Met1982Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,095,871 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.753
• Publications: 2 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1125851).
• BP6: Variant X-32310253-C-T is Benign according to our data. Variant chrX-32310253-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 455915.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.5946G>A	p.Met1982Ile	missense	Exon 42 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.5934G>A	p.Met1978Ile	missense	Exon 42 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.5922G>A	p.Met1974Ile	missense	Exon 42 of 79	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.5946G>A	p.Met1982Ile	missense	Exon 42 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.5934G>A	p.Met1978Ile	missense	Exon 42 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.1914G>A	p.Met638Ile	missense	Exon 14 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181864 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000734

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1095871 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362329

African (AFR) AF: 0.00 AC: 0 AN: 26274

American (AMR) AF: 0.0000856 AC: 3 AN: 35053

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19291

East Asian (EAS) AF: 0.00 AC: 0 AN: 30096

South Asian (SAS) AF: 0.00 AC: 0 AN: 54070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40489

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840544

Other (OTH) AF: 0.00 AC: 0 AN: 45941

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	Duchenne muscular dystrophy (1)
-	1	-	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.75
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.13
Sift	Benign	0.53	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.51		Loss of disorder (P = 0.0796)
MVP		0.25
MPC		0.016
ClinPred		0.043	T
GERP RS		5.3
gMVP		0.14
Mutation Taster		=99/1	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: rs1241760732; hg19: chrX-32328370; COSMIC: COSV63795624;