NM_004006.3:c.1513G>C

Variant names:

• chrX-32595846-C-G
• rs140340626
• NM_004006.3:c.1513G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):​c.1513G>C​(p.Val505Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00155 in 1,197,840 control chromosomes in the GnomAD database, including 1 homozygotes. There are 560 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. V505D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., 34 hem., cov: 23)
  • Exomes 𝑓: 0.0016 (1 hom. 526 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 5.86
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013217211).
• BP6: Variant X-32595846-C-G is Benign according to our data. Variant chrX-32595846-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00109 (122/111848) while in subpopulation NFE AF = 0.00164 (87/53185). AF 95% confidence interval is 0.00136. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 122 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.1513G>C	p.Val505Leu	missense	Exon 13 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1501G>C	p.Val501Leu	missense	Exon 13 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1489G>C	p.Val497Leu	missense	Exon 13 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.1513G>C	p.Val505Leu	missense	Exon 13 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1489G>C	p.Val497Leu	missense	Exon 13 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.247-22000G>C		intron	N/A	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 122 AN: 111793 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00234

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00164

Gnomad OTH AF: 0.000664

GnomAD2 exomes AF: 0.00116 AC: 213 AN: 183182 AF XY: 0.000976

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.000255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00159 AC: 1732 AN: 1085992 Hom.: 1 Cov.: 27 AF XY: 0.00149 AC XY: 526 AN XY: 351958

African (AFR) AF: 0.000115 AC: 3 AN: 26176

American (AMR) AF: 0.000483 AC: 17 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19298

East Asian (EAS) AF: 0.00 AC: 0 AN: 30126

South Asian (SAS) AF: 0.0000557 AC: 3 AN: 53836

European-Finnish (FIN) AF: 0.00286 AC: 116 AN: 40515

Middle Eastern (MID) AF: 0.00267 AC: 11 AN: 4115

European-Non Finnish (NFE) AF: 0.00182 AC: 1515 AN: 831027

Other (OTH) AF: 0.00147 AC: 67 AN: 45715

GnomAD4 genome AF: 0.00109 AC: 122 AN: 111848 Hom.: 0 Cov.: 23 AF XY: 0.00100 AC XY: 34 AN XY: 34016

African (AFR) AF: 0.000194 AC: 6 AN: 30852

American (AMR) AF: 0.00133 AC: 14 AN: 10527

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3534

South Asian (SAS) AF: 0.00 AC: 0 AN: 2686

European-Finnish (FIN) AF: 0.00234 AC: 14 AN: 5988

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

European-Non Finnish (NFE) AF: 0.00164 AC: 87 AN: 53185

Other (OTH) AF: 0.000655 AC: 1 AN: 1526

Alfa AF: 0.00154 Hom.: 25

Bravo AF: 0.00117

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00193 AC: 13

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.00207

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	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	Intellectual disability (1)
-	-	1	Mitochondrial disease (1)
-	-	1	Restrictive cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.88	T
PhyloP100		5.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.089
Sift	Benign	0.13	T
Sift4G	Uncertain	0.034	D
Polyphen		0.55	P
Vest4		0.65
MVP		0.68
MPC		0.049
ClinPred		0.026	T
GERP RS		5.4
gMVP		0.45
Mutation Taster		=93/7	polymorphism (auto)

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: rs140340626; hg19: chrX-32613963;