rs72468638

Variant names:

• chrX-32386455-T-C
• rs72468638
• NM_004006.3:c.4529A>G

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.4529A>G​(p.Lys1510Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,199,881 control chromosomes in the GnomAD database, including 39 homozygotes. There are 1,089 hemizygotes in GnomAD. In-silico tool predicts 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. K1510E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., 148 hem., cov: 22)
  • Exomes 𝑓: 0.0027 (36 hom. 941 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 8.02
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016875923).
• BP6: Variant X-32386455-T-C is Benign according to our data. Variant chrX-32386455-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00289 (321/111132) while in subpopulation EAS AF = 0.0127 (45/3543). AF 95% confidence interval is 0.00975. There are 3 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 321 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.4529A>G	p.Lys1510Arg	missense	Exon 33 of 79	NP_003997.2
	DMD	NM_004009.3		c.4517A>G	p.Lys1506Arg	missense	Exon 33 of 79	NP_004000.1
	DMD	NM_000109.4		c.4505A>G	p.Lys1502Arg	missense	Exon 33 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.4529A>G	p.Lys1510Arg	missense	Exon 33 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.4517A>G	p.Lys1506Arg	missense	Exon 33 of 79	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.497A>G	p.Lys166Arg	missense	Exon 5 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 321 AN: 111083 Hom.: 3 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000762

Gnomad EAS AF: 0.0124

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.00267

GnomAD2 exomes AF: 0.00567 AC: 1029 AN: 181352 AF XY: 0.00479

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000367

Gnomad ASJ exome AF: 0.000269

Gnomad EAS exome AF: 0.0152

Gnomad FIN exome AF: 0.0419

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.00582

GnomAD4 exome AF: 0.00270 AC: 2936 AN: 1088749 Hom.: 36 Cov.: 29 AF XY: 0.00265 AC XY: 941 AN XY: 355373

African (AFR) AF: 0.00 AC: 0 AN: 26191

American (AMR) AF: 0.00 AC: 0 AN: 35054

Ashkenazi Jewish (ASJ) AF: 0.000311 AC: 6 AN: 19263

East Asian (EAS) AF: 0.0243 AC: 731 AN: 30041

South Asian (SAS) AF: 0.000501 AC: 27 AN: 53928

European-Finnish (FIN) AF: 0.0426 AC: 1709 AN: 40140

Middle Eastern (MID) AF: 0.000730 AC: 3 AN: 4108

European-Non Finnish (NFE) AF: 0.000418 AC: 349 AN: 834301

Other (OTH) AF: 0.00243 AC: 111 AN: 45723

GnomAD4 genome AF: 0.00289 AC: 321 AN: 111132 Hom.: 3 Cov.: 22 AF XY: 0.00441 AC XY: 148 AN XY: 33562

African (AFR) AF: 0.00 AC: 0 AN: 30844

American (AMR) AF: 0.00 AC: 0 AN: 10395

Ashkenazi Jewish (ASJ) AF: 0.000762 AC: 2 AN: 2626

East Asian (EAS) AF: 0.0127 AC: 45 AN: 3543

South Asian (SAS) AF: 0.00186 AC: 5 AN: 2685

European-Finnish (FIN) AF: 0.0364 AC: 218 AN: 5988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000912 AC: 48 AN: 52636

Other (OTH) AF: 0.00198 AC: 3 AN: 1515

Alfa AF: 0.00140 Hom.: 68

Bravo AF: 0.000926

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00509 AC: 617

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Duchenne muscular dystrophy (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (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	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.34	T
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.19
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.44
MVP		0.76
MPC		0.084
ClinPred		0.036	T
GERP RS		5.5
gMVP		0.23
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72468638; hg19: chrX-32404572;