rs34563188

Variant names:

• chrX-32545330-G-A
• rs34563188
• NM_004006.3:c.1997C>T

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.1997C>T​(p.Ser666Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,207,831 control chromosomes in the GnomAD database, including 6 homozygotes. There are 205 hemizygotes in GnomAD. In-silico tool predicts 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. S666P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., 107 hem., cov: 23)
  • Exomes 𝑓: 0.00043 (3 hom. 98 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 8.75
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009159237).
• BP6: Variant X-32545330-G-A is Benign according to our data. Variant chrX-32545330-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94487.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00421 (470/111684) while in subpopulation AFR AF = 0.0145 (447/30737). AF 95% confidence interval is 0.0134. There are 3 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 470 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.1997C>T	p.Ser666Leu	missense	Exon 17 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1985C>T	p.Ser662Leu	missense	Exon 17 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1973C>T	p.Ser658Leu	missense	Exon 17 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.1997C>T	p.Ser666Leu	missense	Exon 17 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1973C>T	p.Ser658Leu	missense	Exon 17 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.1985C>T	p.Ser662Leu	missense	Exon 17 of 79	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 472 AN: 111627 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

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: 0.00332

GnomAD2 exomes AF: 0.00111 AC: 203 AN: 182764 AF XY: 0.000742

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.000432 AC: 473 AN: 1096147 Hom.: 3 Cov.: 31 AF XY: 0.000271 AC XY: 98 AN XY: 361829

African (AFR) AF: 0.0150 AC: 395 AN: 26329

American (AMR) AF: 0.000483 AC: 17 AN: 35171

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19344

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.0000555 AC: 3 AN: 54086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40487

Middle Eastern (MID) AF: 0.000500 AC: 2 AN: 3998

European-Non Finnish (NFE) AF: 0.00000595 AC: 5 AN: 840551

Other (OTH) AF: 0.00111 AC: 51 AN: 45993

GnomAD4 genome AF: 0.00421 AC: 470 AN: 111684 Hom.: 3 Cov.: 23 AF XY: 0.00316 AC XY: 107 AN XY: 33900

African (AFR) AF: 0.0145 AC: 447 AN: 30737

American (AMR) AF: 0.00153 AC: 16 AN: 10475

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00 AC: 0 AN: 2667

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6071

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

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53104

Other (OTH) AF: 0.00328 AC: 5 AN: 1526

Alfa AF: 0.000859 Hom.: 44

Bravo AF: 0.00492

ESP6500AA AF: 0.0159 AC: 61

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00131 AC: 159

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
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Cardiomyopathy (1)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	-0.17	T
PhyloP100		8.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.025	D
Polyphen		0.98	D
Vest4		0.69
MVP		0.83
MPC		0.088
ClinPred		0.024	T
GERP RS		5.6
gMVP		0.28
Mutation Taster		=98/2	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: rs34563188; hg19: chrX-32563447; COSMIC: COSV99053213;