X-31773947-T-C

Variant names:

• chrX-31773947-T-C
• rs72466585
• NM_004006.3:c.7542+13A>G

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.7542+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,193,378 control chromosomes in the GnomAD database, including 28 homozygotes. There are 2,304 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., 119 hem., cov: 21)
  • Exomes 𝑓: 0.0062 (27 hom. 2185 hem.)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0150
• Publications: 3 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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=-0.87).
• BP6: Variant X-31773947-T-C is Benign according to our data. Variant chrX-31773947-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00412 (451/109466) while in subpopulation AMR AF = 0.00808 (81/10022). AF 95% confidence interval is 0.00666. There are 1 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 451 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.7542+13A>G		intron	N/A	NP_003997.2
	DMD	NM_004009.3		c.7530+13A>G		intron	N/A	NP_004000.1
	DMD	NM_000109.4		c.7518+13A>G		intron	N/A	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.7542+13A>G		intron	N/A	ENSP00000354923.3
	DMD	ENST00000471779.1	TSL:1	n.*206+13A>G		intron	N/A	ENSP00000417075.1
	DMD	ENST00000378677.6	TSL:5	c.7530+13A>G		intron	N/A	ENSP00000367948.2

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 450 AN: 109416 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.000698

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000357

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00637

Gnomad OTH AF: 0.00751

GnomAD2 exomes AF: 0.00384 AC: 697 AN: 181738 AF XY: 0.00406

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00443

Gnomad ASJ exome AF: 0.000269

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000752

Gnomad NFE exome AF: 0.00643

Gnomad OTH exome AF: 0.00469

GnomAD4 exome AF: 0.00617 AC: 6693 AN: 1083912 Hom.: 27 Cov.: 28 AF XY: 0.00623 AC XY: 2185 AN XY: 350706

African (AFR) AF: 0.000880 AC: 23 AN: 26130

American (AMR) AF: 0.00469 AC: 165 AN: 35151

Ashkenazi Jewish (ASJ) AF: 0.000207 AC: 4 AN: 19287

East Asian (EAS) AF: 0.00 AC: 0 AN: 30139

South Asian (SAS) AF: 0.0000372 AC: 2 AN: 53804

European-Finnish (FIN) AF: 0.000742 AC: 30 AN: 40439

Middle Eastern (MID) AF: 0.00268 AC: 11 AN: 4102

European-Non Finnish (NFE) AF: 0.00750 AC: 6216 AN: 829241

Other (OTH) AF: 0.00530 AC: 242 AN: 45619

GnomAD4 genome AF: 0.00412 AC: 451 AN: 109466 Hom.: 1 Cov.: 21 AF XY: 0.00375 AC XY: 119 AN XY: 31728

African (AFR) AF: 0.000696 AC: 21 AN: 30151

American (AMR) AF: 0.00808 AC: 81 AN: 10022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2627

East Asian (EAS) AF: 0.00 AC: 0 AN: 3476

South Asian (SAS) AF: 0.00 AC: 0 AN: 2495

European-Finnish (FIN) AF: 0.000357 AC: 2 AN: 5606

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

European-Non Finnish (NFE) AF: 0.00637 AC: 336 AN: 52711

Other (OTH) AF: 0.00742 AC: 11 AN: 1483

Alfa AF: 0.00451 Hom.: 38

Bravo AF: 0.00461

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Dilated cardiomyopathy 3B (1)
-	-	1	Duchenne muscular dystrophy (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	-0.87
CADD	Benign	3.5
DANN	Benign	0.62
PhyloP100		-0.015
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: rs72466585; hg19: chrX-31792064;