rs41303187

Variant names:

• chrX-31178825-G-A
• rs41303187
• NM_004006.3:c.10087-20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):​c.10087-20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 1,206,506 control chromosomes in the GnomAD database, including 2 homozygotes. There are 987 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., 54 hem., cov: 23)
  • Exomes 𝑓: 0.0027 (2 hom. 933 hem.)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.58
• 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: Orphanet, Ambry Genetics
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-31178825-G-A is Benign according to our data. Variant chrX-31178825-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94423.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 = 0.00197 (221/112131) while in subpopulation NFE AF = 0.00357 (190/53171). AF 95% confidence interval is 0.00316. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 221 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.10087-20C>T		intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.10075-20C>T		intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.10063-20C>T		intron	N/A	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.10087-20C>T		intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000378723.7	TSL:1	c.883-20C>T		intron	N/A	ENSP00000367997.3	P11532-6
	DMD	ENST00000361471.8	TSL:1	c.883-20C>T		intron	N/A	ENSP00000354464.4	P11532-5

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 221 AN: 112078 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.00194 AC: 350 AN: 180732 AF XY: 0.00189

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.000585

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.0000724

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00358

Gnomad OTH exome AF: 0.00178

GnomAD4 exome AF: 0.00270 AC: 2954 AN: 1094375 Hom.: 2 Cov.: 29 AF XY: 0.00259 AC XY: 933 AN XY: 360383

African (AFR) AF: 0.000228 AC: 6 AN: 26283

American (AMR) AF: 0.000712 AC: 25 AN: 35127

Ashkenazi Jewish (ASJ) AF: 0.0000519 AC: 1 AN: 19275

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30088

South Asian (SAS) AF: 0.000537 AC: 29 AN: 53984

European-Finnish (FIN) AF: 0.00236 AC: 95 AN: 40325

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00320 AC: 2687 AN: 839276

Other (OTH) AF: 0.00240 AC: 110 AN: 45898

GnomAD4 genome AF: 0.00197 AC: 221 AN: 112131 Hom.: 0 Cov.: 23 AF XY: 0.00157 AC XY: 54 AN XY: 34303

African (AFR) AF: 0.000356 AC: 11 AN: 30921

American (AMR) AF: 0.000662 AC: 7 AN: 10580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

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

European-Finnish (FIN) AF: 0.00180 AC: 11 AN: 6128

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

European-Non Finnish (NFE) AF: 0.00357 AC: 190 AN: 53171

Other (OTH) AF: 0.00131 AC: 2 AN: 1527

Alfa AF: 0.00182 Hom.: 12

Bravo AF: 0.00173

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	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
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.2
DANN	Benign	0.77
PhyloP100		1.6
BranchPoint Hunter		3.0
Mutation Taster		=99/1	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41303187;

hg19: chrX-31196942;