rs753639717

Variant names:

• chrX-32411903-C-A
• rs753639717
• NM_004006.3:c.4082G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-32411903-C-A
• chrX-32411903-C-G
• chrX-32411903-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6_Very_Strong BS2_Supporting

The NM_004006.3(DMD):​c.4082G>T​(p.Arg1361Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000456 in 1,097,427 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1361K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.66
• Publications: 4 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35188264).
• BP6: Variant X-32411903-C-A is Benign according to our data. Variant chrX-32411903-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 739306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 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.

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.4082G>T	p.Arg1361Met	missense	Exon 30 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.4070G>T	p.Arg1357Met	missense	Exon 30 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.4058G>T	p.Arg1353Met	missense	Exon 30 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.4082G>T	p.Arg1361Met	missense	Exon 30 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.4070G>T	p.Arg1357Met	missense	Exon 30 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.50G>T	p.Arg17Met	missense	Exon 2 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000658 AC: 12 AN: 182471 AF XY: 0.000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000873

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097427 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 362939

African (AFR) AF: 0.00 AC: 0 AN: 26389

American (AMR) AF: 0.00 AC: 0 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.000166 AC: 5 AN: 30121

South Asian (SAS) AF: 0.00 AC: 0 AN: 54101

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40491

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841583

Other (OTH) AF: 0.00 AC: 0 AN: 46055

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Duchenne muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.55	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.54	T
PhyloP100		3.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.94	P
Vest4		0.53
MutPred		0.52		Loss of ubiquitination at K1363 (P = 0.0366)
MVP		0.62
MPC		0.11
ClinPred		0.48	T
GERP RS		4.8
PromoterAI		0.0062	Neutral
gMVP		0.60
Mutation Taster		=88/12	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: rs753639717; hg19: chrX-32430020;