rs398123965

Variant names:

• chrX-32380611-C-T
• rs398123965
• NM_004006.3:c.4744G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-32380611-C-T
• chrX-32380611-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004006.3(DMD):​c.4744G>A​(p.Val1582Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,208,091 control chromosomes in the GnomAD database, including 1 homozygotes. There are 55 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1582A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.00011 (1 hom. 53 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 2.62
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014814973).
• BP6: Variant X-32380611-C-T is Benign according to our data. Variant chrX-32380611-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94637.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000107 (117/1096586) while in subpopulation SAS AF = 0.00163 (88/54099). AF 95% confidence interval is 0.00135. There are 1 homozygotes in GnomAdExome4. There are 53 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 117 XL,AD gene.

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.4744G>A	p.Val1582Ile	missense	Exon 34 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.4732G>A	p.Val1578Ile	missense	Exon 34 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.4720G>A	p.Val1574Ile	missense	Exon 34 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.4744G>A	p.Val1582Ile	missense	Exon 34 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.4732G>A	p.Val1578Ile	missense	Exon 34 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.712G>A	p.Val238Ile	missense	Exon 6 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.0000359 AC: 4 AN: 111451 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00149

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 27 AN: 182472 AF XY: 0.000208

Gnomad AFR exome AF: 0.0000761

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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000107 AC: 117 AN: 1096586 Hom.: 1 Cov.: 29 AF XY: 0.000146 AC XY: 53 AN XY: 362306

African (AFR) AF: 0.00 AC: 0 AN: 26357

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19356

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30151

South Asian (SAS) AF: 0.00163 AC: 88 AN: 54099

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40136

Middle Eastern (MID) AF: 0.000968 AC: 4 AN: 4131

European-Non Finnish (NFE) AF: 0.0000262 AC: 22 AN: 841103

Other (OTH) AF: 0.0000434 AC: 2 AN: 46055

GnomAD4 genome AF: 0.0000359 AC: 4 AN: 111505 Hom.: 0 Cov.: 22 AF XY: 0.0000592 AC XY: 2 AN XY: 33757

African (AFR) AF: 0.00 AC: 0 AN: 30783

American (AMR) AF: 0.00 AC: 0 AN: 10461

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3533

South Asian (SAS) AF: 0.00150 AC: 4 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6007

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52994

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 3B (1)
-	-	1	DMD-related disorder (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	20
DANN	Benign	0.32
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.6
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.064
Sift	Benign	0.74	T
Sift4G	Benign	0.95	T
Polyphen		0.0070	B
Vest4		0.18
MutPred		0.45		Gain of catalytic residue at L1587 (P = 0.0584)
MVP		0.39
MPC		0.016
ClinPred		0.058	T
GERP RS		4.5
gMVP		0.065
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: rs398123965; hg19: chrX-32398728; COSMIC: COSV105278700;