rs182708940

Variant names:

• chrX-32573783-C-T
• rs182708940
• NM_004006.3:c.1666G>A

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.1666G>A​(p.Asp556Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,210,208 control chromosomes in the GnomAD database, including 1 homozygotes. There are 94 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. D556G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 10 hem., cov: 23)
  • Exomes 𝑓: 0.00022 (1 hom. 84 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.32
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008932203).
• BP6: Variant X-32573783-C-T is Benign according to our data. Variant chrX-32573783-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 201729.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 = 0.000276 (31/112256) while in subpopulation EAS AF = 0.00786 (28/3561). AF 95% confidence interval is 0.00559. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 31 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.1666G>A	p.Asp556Asn	missense	Exon 14 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1654G>A	p.Asp552Asn	missense	Exon 14 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1642G>A	p.Asp548Asn	missense	Exon 14 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.1666G>A	p.Asp556Asn	missense	Exon 14 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1642G>A	p.Asp548Asn	missense	Exon 14 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.310G>A	p.Asp104Asn	missense	Exon 4 of 5	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 31 AN: 112203 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00784

Gnomad SAS AF: 0.000366

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000701 AC: 128 AN: 182663 AF XY: 0.000550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00860

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000216 AC: 237 AN: 1097952 Hom.: 1 Cov.: 30 AF XY: 0.000231 AC XY: 84 AN XY: 363356

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.00619 AC: 187 AN: 30192

South Asian (SAS) AF: 0.000499 AC: 27 AN: 54097

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40499

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 841996

Other (OTH) AF: 0.000304 AC: 14 AN: 46083

GnomAD4 genome AF: 0.000276 AC: 31 AN: 112256 Hom.: 0 Cov.: 23 AF XY: 0.000291 AC XY: 10 AN XY: 34420

African (AFR) AF: 0.00 AC: 0 AN: 30906

American (AMR) AF: 0.00 AC: 0 AN: 10561

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

East Asian (EAS) AF: 0.00786 AC: 28 AN: 3561

South Asian (SAS) AF: 0.000367 AC: 1 AN: 2722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6142

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

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53285

Other (OTH) AF: 0.00 AC: 0 AN: 1524

Alfa AF: 0.000548 Hom.: 9

Bravo AF: 0.000582

ExAC AF: 0.000643 AC: 78

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0089	T
MetaSVM	Uncertain	0.34	D
PhyloP100		4.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.17
Sift	Benign	0.088	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.0030	B
Vest4		0.13
MVP		0.91
MPC		0.11
ClinPred		0.098	T
GERP RS		5.4
gMVP		0.13
Mutation Taster		=97/3	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: rs182708940; hg19: chrX-32591900;