rs200887855

Variant names:

• chrX-32362932-T-A
• rs200887855
• NM_004006.3:c.5181A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-32362932-T-A
• chrX-32362932-T-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004006.3(DMD):​c.5181A>T​(p.Ile1727Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,208,982 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 74 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).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., 17 hem., cov: 22)
  • Exomes 𝑓: 0.00012 (0 hom. 57 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.188
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant X-32362932-T-A is Benign according to our data. Variant chrX-32362932-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94655.
• BP7: Synonymous conserved (PhyloP=-0.188 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000386 (43/111265) while in subpopulation AMR AF = 0.0028 (29/10365). AF 95% confidence interval is 0.002. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 43 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.5181A>T	p.Ile1727Ile	synonymous	Exon 37 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.5169A>T	p.Ile1723Ile	synonymous	Exon 37 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.5157A>T	p.Ile1719Ile	synonymous	Exon 37 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.5181A>T	p.Ile1727Ile	synonymous	Exon 37 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.5169A>T	p.Ile1723Ile	synonymous	Exon 37 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.1149A>T	p.Ile383Ile	synonymous	Exon 9 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.000387 AC: 43 AN: 111207 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00293

Gnomad AMR AF: 0.00280

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000169

Gnomad MID AF: 0.00426

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000181 AC: 33 AN: 181927 AF XY: 0.000240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.000198

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 130 AN: 1097717 Hom.: 0 Cov.: 31 AF XY: 0.000157 AC XY: 57 AN XY: 363139

African (AFR) AF: 0.00 AC: 0 AN: 26396

American (AMR) AF: 0.000426 AC: 15 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30169

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54104

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40504

Middle Eastern (MID) AF: 0.00266 AC: 11 AN: 4132

European-Non Finnish (NFE) AF: 0.000115 AC: 97 AN: 841779

Other (OTH) AF: 0.0000217 AC: 1 AN: 46080

GnomAD4 genome AF: 0.000386 AC: 43 AN: 111265 Hom.: 0 Cov.: 22 AF XY: 0.000508 AC XY: 17 AN XY: 33449

African (AFR) AF: 0.00 AC: 0 AN: 30607

American (AMR) AF: 0.00280 AC: 29 AN: 10365

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3525

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

European-Finnish (FIN) AF: 0.000169 AC: 1 AN: 5924

Middle Eastern (MID) AF: 0.00467 AC: 1 AN: 214

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53127

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.000203 Hom.: 7

Bravo AF: 0.000408

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Duchenne muscular dystrophy (2)
-	-	2	not specified (2)
-	-	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
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.9
DANN	Benign	0.73
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs200887855; hg19: chrX-32381049;