rs2270672

Variant names:

• chrX-31657979-G-A
• rs2270672
• NM_004006.3:c.8027+11C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004006.3(DMD):​c.8027+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,201,414 control chromosomes in the GnomAD database, including 50,207 homozygotes. There are 137,658 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (4449 hom., 10714 hem., cov: 22)
  • Exomes 𝑓: 0.35 (45758 hom. 126944 hem.)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.00
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-31657979-G-A is Benign according to our data. Variant chrX-31657979-G-A is described in ClinVar as Benign. ClinVar VariationId is 94783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

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.8027+11C>T		intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.8015+11C>T		intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.8003+11C>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.8027+11C>T		intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.8015+11C>T		intron	N/A	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.3995+11C>T		intron	N/A	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.331 AC: 36514 AN: 110243 Hom.: 4449 Cov.: 22

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.302

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.297

GnomAD2 exomes AF: 0.332 AC: 60352 AN: 181665 AF XY: 0.342

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.318

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.352 AC: 383534 AN: 1091114 Hom.: 45758 Cov.: 29 AF XY: 0.355 AC XY: 126944 AN XY: 357886

African (AFR) AF: 0.323 AC: 8493 AN: 26269

American (AMR) AF: 0.187 AC: 6576 AN: 35142

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 6039 AN: 19321

East Asian (EAS) AF: 0.289 AC: 8701 AN: 30157

South Asian (SAS) AF: 0.435 AC: 23457 AN: 53967

European-Finnish (FIN) AF: 0.431 AC: 17436 AN: 40458

Middle Eastern (MID) AF: 0.273 AC: 1127 AN: 4121

European-Non Finnish (NFE) AF: 0.354 AC: 296296 AN: 835862

Other (OTH) AF: 0.336 AC: 15409 AN: 45817

GnomAD4 genome AF: 0.331 AC: 36518 AN: 110300 Hom.: 4449 Cov.: 22 AF XY: 0.329 AC XY: 10714 AN XY: 32612

African (AFR) AF: 0.315 AC: 9559 AN: 30336

American (AMR) AF: 0.233 AC: 2422 AN: 10410

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 851 AN: 2636

East Asian (EAS) AF: 0.290 AC: 1007 AN: 3477

South Asian (SAS) AF: 0.431 AC: 1114 AN: 2587

European-Finnish (FIN) AF: 0.421 AC: 2419 AN: 5752

Middle Eastern (MID) AF: 0.306 AC: 66 AN: 216

European-Non Finnish (NFE) AF: 0.352 AC: 18533 AN: 52704

Other (OTH) AF: 0.293 AC: 442 AN: 1510

Alfa AF: 0.342 Hom.: 26460

Bravo AF: 0.317

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Dilated cardiomyopathy 3B (2)
-	-	2	Duchenne muscular dystrophy (2)
-	-	2	not provided (2)
-	-	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	-0.70
CADD	Benign	10
DANN	Benign	0.68
PhyloP100		1.0
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs2270672; hg19: chrX-31676096;