rs187926894

Variant names:

• chrX-32491324-T-A
• rs187926894
• NM_004006.3:c.2575A>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004006.3(DMD):​c.2575A>T​(p.Thr859Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,209,203 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 54 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T859T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 6 hem., cov: 24)
  • Exomes 𝑓: 0.00012 (0 hom. 48 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0180
• Publications: 2 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

ENSG00000297605 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03745702).
• BP6: Variant X-32491324-T-A is Benign according to our data. Variant chrX-32491324-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 195494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 17 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.2575A>T	p.Thr859Ser	missense	Exon 20 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.2563A>T	p.Thr855Ser	missense	Exon 20 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.2551A>T	p.Thr851Ser	missense	Exon 20 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.2575A>T	p.Thr859Ser	missense	Exon 20 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.2563A>T	p.Thr855Ser	missense	Exon 20 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-126125A>T		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.000153 AC: 17 AN: 111320 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000959

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: 0.000264

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000114 AC: 21 AN: 183485 AF XY: 0.000132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 128 AN: 1097825 Hom.: 0 Cov.: 30 AF XY: 0.000132 AC XY: 48 AN XY: 363185

African (AFR) AF: 0.0000379 AC: 1 AN: 26396

American (AMR) AF: 0.0000852 AC: 3 AN: 35205

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00 AC: 0 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.000138 AC: 116 AN: 841758

Other (OTH) AF: 0.000174 AC: 8 AN: 46086

GnomAD4 genome AF: 0.000153 AC: 17 AN: 111378 Hom.: 0 Cov.: 24 AF XY: 0.000178 AC XY: 6 AN XY: 33642

African (AFR) AF: 0.0000653 AC: 2 AN: 30632

American (AMR) AF: 0.0000958 AC: 1 AN: 10441

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3533

South Asian (SAS) AF: 0.00 AC: 0 AN: 2683

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5966

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

European-Non Finnish (NFE) AF: 0.000264 AC: 14 AN: 53061

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.000170 Hom.: 3

Bravo AF: 0.000162

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (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	0.086
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.98
CADD	Benign	5.3
DANN	Benign	0.34
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.018
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.030
Sift	Benign	0.91	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.34		Loss of phosphorylation at T859 (P = 0.0696)
MVP		0.24
MPC		0.016
ClinPred		0.025	T
GERP RS		-5.5
gMVP		0.083
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs187926894; hg19: chrX-32509441;