rs1800281

Variant names:

• chrX-31147283-G-A
• rs1800281
• NM_004006.3:c.10789C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-31147283-G-A
• chrX-31147283-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):​c.10789C>T​(p.Leu3597Leu) variant causes a synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 1,208,653 control chromosomes in the GnomAD database, including 24 homozygotes. There are 2,429 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L3597L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., 146 hem., cov: 22)
  • Exomes 𝑓: 0.0067 (20 hom. 2283 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 10.0
• 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

ENSG00000297249 (HGNC:):

ACMG classification

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

• BP6: Variant X-31147283-G-A is Benign according to our data. Variant chrX-31147283-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94446.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0048 (534/111150) while in subpopulation NFE AF = 0.00737 (391/53024). AF 95% confidence interval is 0.00677. There are 4 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 534 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.10789C>T	p.Leu3597Leu	synonymous	Exon 75 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.10777C>T	p.Leu3593Leu	synonymous	Exon 75 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.10765C>T	p.Leu3589Leu	synonymous	Exon 75 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.10789C>T	p.Leu3597Leu	synonymous	Exon 75 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378723.7	TSL:1	c.1585C>T	p.Leu529Leu	synonymous	Exon 14 of 17	ENSP00000367997.3	P11532-6
	DMD	ENST00000361471.8	TSL:1	c.1546C>T	p.Leu516Leu	synonymous	Exon 13 of 16	ENSP00000354464.4	P11532-5

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 534 AN: 111097 Hom.: 4 Cov.: 22

Gnomad AFR AF: 0.000787

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00469

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00115

Gnomad FIN AF: 0.00799

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.00737

Gnomad OTH AF: 0.00868

GnomAD2 exomes AF: 0.00476 AC: 871 AN: 183079 AF XY: 0.00457

Gnomad AFR exome AF: 0.000684

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00976

Gnomad NFE exome AF: 0.00732

Gnomad OTH exome AF: 0.00509

GnomAD4 exome AF: 0.00669 AC: 7340 AN: 1097503 Hom.: 20 Cov.: 31 AF XY: 0.00629 AC XY: 2283 AN XY: 362907

African (AFR) AF: 0.000758 AC: 20 AN: 26392

American (AMR) AF: 0.00301 AC: 106 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 24 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30183

South Asian (SAS) AF: 0.000277 AC: 15 AN: 54115

European-Finnish (FIN) AF: 0.00906 AC: 367 AN: 40492

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4135

European-Non Finnish (NFE) AF: 0.00774 AC: 6511 AN: 841525

Other (OTH) AF: 0.00632 AC: 291 AN: 46075

GnomAD4 genome AF: 0.00480 AC: 534 AN: 111150 Hom.: 4 Cov.: 22 AF XY: 0.00438 AC XY: 146 AN XY: 33330

African (AFR) AF: 0.000785 AC: 24 AN: 30579

American (AMR) AF: 0.00468 AC: 49 AN: 10468

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 5 AN: 2655

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

South Asian (SAS) AF: 0.00115 AC: 3 AN: 2599

European-Finnish (FIN) AF: 0.00799 AC: 47 AN: 5881

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.00737 AC: 391 AN: 53024

Other (OTH) AF: 0.00858 AC: 13 AN: 1516

Alfa AF: 0.00542 Hom.: 80

Bravo AF: 0.00466

EpiCase AF: 0.00638

EpiControl AF: 0.00818

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	2	Duchenne muscular dystrophy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.5
DANN	Benign	0.82
PhyloP100		10
Mutation Taster		=65/35	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1800281; hg19: chrX-31165400;