rs41305353

Variant names:

• chrX-31478314-T-A
• rs41305353
• NM_004006.3:c.8729A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-31478314-T-A
• chrX-31478314-T-C

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.8729A>T​(p.Glu2910Val) variant causes a missense change. The variant allele was found at a frequency of 0.0146 in 1,209,357 control chromosomes in the GnomAD database, including 183 homozygotes. There are 5,332 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2910K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (73 hom., 849 hem., cov: 22)
  • Exomes 𝑓: 0.013 (110 hom. 4483 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:17
• Conservation: PhyloP100: 5.93
• Publications: 14 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 (MetaRNN=0.010023415).
• BP6: Variant X-31478314-T-A is Benign according to our data. Variant chrX-31478314-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 11267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 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.8729A>T	p.Glu2910Val	missense	Exon 59 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.8717A>T	p.Glu2906Val	missense	Exon 59 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.8705A>T	p.Glu2902Val	missense	Exon 59 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.8729A>T	p.Glu2910Val	missense	Exon 59 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.8717A>T	p.Glu2906Val	missense	Exon 59 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.4697A>T	p.Glu1566Val	missense	Exon 31 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 3070 AN: 111177 Hom.: 73 Cov.: 22

Gnomad AFR AF: 0.0669

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0186

Gnomad EAS AF: 0.0424

Gnomad SAS AF: 0.00883

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.00952

Gnomad OTH AF: 0.0228

GnomAD2 exomes AF: 0.0209 AC: 3833 AN: 183174 AF XY: 0.0176

Gnomad AFR exome AF: 0.0731

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0168

Gnomad EAS exome AF: 0.0457

Gnomad FIN exome AF: 0.0194

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0132 AC: 14526 AN: 1098124 Hom.: 110 Cov.: 34 AF XY: 0.0123 AC XY: 4483 AN XY: 363480

African (AFR) AF: 0.0690 AC: 1821 AN: 26403

American (AMR) AF: 0.0243 AC: 854 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 343 AN: 19381

East Asian (EAS) AF: 0.0417 AC: 1259 AN: 30205

South Asian (SAS) AF: 0.0118 AC: 640 AN: 54147

European-Finnish (FIN) AF: 0.0186 AC: 753 AN: 40528

Middle Eastern (MID) AF: 0.0114 AC: 47 AN: 4137

European-Non Finnish (NFE) AF: 0.00951 AC: 8007 AN: 842028

Other (OTH) AF: 0.0174 AC: 802 AN: 46093

GnomAD4 genome AF: 0.0276 AC: 3075 AN: 111233 Hom.: 73 Cov.: 22 AF XY: 0.0254 AC XY: 849 AN XY: 33429

African (AFR) AF: 0.0670 AC: 2047 AN: 30575

American (AMR) AF: 0.0170 AC: 177 AN: 10429

Ashkenazi Jewish (ASJ) AF: 0.0186 AC: 49 AN: 2640

East Asian (EAS) AF: 0.0422 AC: 149 AN: 3532

South Asian (SAS) AF: 0.00886 AC: 23 AN: 2596

European-Finnish (FIN) AF: 0.0145 AC: 86 AN: 5922

Middle Eastern (MID) AF: 0.0230 AC: 5 AN: 217

European-Non Finnish (NFE) AF: 0.00953 AC: 506 AN: 53121

Other (OTH) AF: 0.0218 AC: 33 AN: 1513

Alfa AF: 0.0155 Hom.: 365

Bravo AF: 0.0316

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00831 AC: 24

ESP6500AA AF: 0.0686 AC: 263

ESP6500EA AF: 0.00847 AC: 57

ExAC AF: 0.0208 AC: 2524

EpiCase AF: 0.00841

EpiControl AF: 0.00741

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	3	Duchenne muscular dystrophy (4)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.30	T
Polyphen		0.075	B
Vest4		0.27
MPC		0.056
ClinPred		0.045	T
GERP RS		5.4
gMVP		0.25
Mutation Taster		=97/3	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: rs41305353; hg19: chrX-31496431; COSMIC: COSV104414666;