rs150199251

Variant names:

• chrX-32573611-T-A
• rs150199251
• NM_004006.3:c.1731A>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.1731A>T​(p.Glu577Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,209,907 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 59 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. E577G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., 24 hem., cov: 23)
  • Exomes 𝑓: 0.000094 (0 hom. 35 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.30
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017938107).
• BP6: Variant X-32573611-T-A is Benign according to our data. Variant chrX-32573611-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94478.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000703 (79/112386) while in subpopulation AFR AF = 0.00233 (72/30959). AF 95% confidence interval is 0.00189. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 79 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.1731A>T	p.Glu577Asp	missense	Exon 15 of 79	NP_003997.2
	DMD	NM_004009.3		c.1719A>T	p.Glu573Asp	missense	Exon 15 of 79	NP_004000.1
	DMD	NM_000109.4		c.1707A>T	p.Glu569Asp	missense	Exon 15 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.1731A>T	p.Glu577Asp	missense	Exon 15 of 79	ENSP00000354923.3
	DMD	ENST00000288447.9	TSL:1	c.1707A>T	p.Glu569Asp	missense	Exon 15 of 18	ENSP00000288447.4
	DMD	ENST00000447523.1	TSL:1	c.375A>T	p.Glu125Asp	missense splice_region	Exon 5 of 5	ENSP00000395904.1

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 79 AN: 112331 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000379

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: 0.0000563

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000191 AC: 35 AN: 183229 AF XY: 0.000162

Gnomad AFR exome AF: 0.00160

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000938 AC: 103 AN: 1097521 Hom.: 0 Cov.: 30 AF XY: 0.0000964 AC XY: 35 AN XY: 362929

African (AFR) AF: 0.00250 AC: 66 AN: 26384

American (AMR) AF: 0.000284 AC: 10 AN: 35188

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

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

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 841527

Other (OTH) AF: 0.000261 AC: 12 AN: 46065

GnomAD4 genome AF: 0.000703 AC: 79 AN: 112386 Hom.: 0 Cov.: 23 AF XY: 0.000695 AC XY: 24 AN XY: 34546

African (AFR) AF: 0.00233 AC: 72 AN: 30959

American (AMR) AF: 0.000379 AC: 4 AN: 10560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3597

South Asian (SAS) AF: 0.00 AC: 0 AN: 2705

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6165

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

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53308

Other (OTH) AF: 0.00 AC: 0 AN: 1530

Alfa AF: 0.000167 Hom.: 2

Bravo AF: 0.000816

ESP6500AA AF: 0.00157 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.76	T
PhyloP100		1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.062
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.052	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.32		Loss of disorder (P = 0.1803)
MVP		0.73
MPC		0.016
ClinPred		0.038	T
GERP RS		1.3
gMVP		0.21
Mutation Taster		=97/3	polymorphism

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: rs150199251; hg19: chrX-32591728;