rs143184877

Variant names:

• chrX-32438342-G-A
• rs143184877
• NM_004006.3:c.3970C>T

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.3970C>T​(p.Arg1324Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000368 in 1,209,433 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 117 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. R1324H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., 52 hem., cov: 23)
  • Exomes 𝑓: 0.00022 (0 hom. 65 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 5.30
• 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: 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=0.02620092).
• BP6: Variant X-32438342-G-A is Benign according to our data. Variant chrX-32438342-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00186 (208/111658) while in subpopulation AFR AF = 0.00659 (203/30781). AF 95% confidence interval is 0.00585. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 208 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.3970C>T	p.Arg1324Cys	missense	Exon 29 of 79	NP_003997.2
	DMD	NM_004009.3		c.3958C>T	p.Arg1320Cys	missense	Exon 29 of 79	NP_004000.1
	DMD	NM_000109.4		c.3946C>T	p.Arg1316Cys	missense	Exon 29 of 79	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.3970C>T	p.Arg1324Cys	missense	Exon 29 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.3958C>T	p.Arg1320Cys	missense	Exon 29 of 79	ENSP00000367948.2
	DMD	ENST00000420596.5	TSL:5	c.94-73143C>T		intron	N/A	ENSP00000399897.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 207 AN: 111606 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000953

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.00132

GnomAD2 exomes AF: 0.000558 AC: 102 AN: 182953 AF XY: 0.000251

Gnomad AFR exome AF: 0.00715

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000216 AC: 237 AN: 1097775 Hom.: 0 Cov.: 30 AF XY: 0.000179 AC XY: 65 AN XY: 363219

African (AFR) AF: 0.00758 AC: 200 AN: 26390

American (AMR) AF: 0.0000284 AC: 1 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30157

South Asian (SAS) AF: 0.00 AC: 0 AN: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

Middle Eastern (MID) AF: 0.00363 AC: 15 AN: 4135

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841785

Other (OTH) AF: 0.000391 AC: 18 AN: 46075

GnomAD4 genome AF: 0.00186 AC: 208 AN: 111658 Hom.: 0 Cov.: 23 AF XY: 0.00153 AC XY: 52 AN XY: 33886

African (AFR) AF: 0.00659 AC: 203 AN: 30781

American (AMR) AF: 0.0000952 AC: 1 AN: 10503

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2628

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2663

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5999

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53110

Other (OTH) AF: 0.00131 AC: 2 AN: 1531

Alfa AF: 0.000316 Hom.: 12

Bravo AF: 0.00216

ESP6500AA AF: 0.00809 AC: 31

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000667 AC: 81

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	2	Duchenne muscular dystrophy (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (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	0.23
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.96	T
PhyloP100		5.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.92
MPC		0.12
ClinPred		0.088	T
GERP RS		5.8
gMVP		0.33
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143184877; hg19: chrX-32456459; COSMIC: COSV63734343;