rs3827462

Variant names:

• chrX-32463465-T-A
• rs3827462
• NM_004006.3:c.3406A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-32463465-T-A
• chrX-32463465-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.3406A>T​(p.Thr1136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00612 in 1,206,084 control chromosomes in the GnomAD database, including 147 homozygotes. There are 3,123 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., 255 hem., cov: 23)
  • Exomes 𝑓: 0.0062 (141 hom. 2868 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.140
• Publications: 7 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=0.003510654).
• BP6: Variant X-32463465-T-A is Benign according to our data. Variant chrX-32463465-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0673 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.3406A>T	p.Thr1136Ser	missense	Exon 25 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.3394A>T	p.Thr1132Ser	missense	Exon 25 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.3382A>T	p.Thr1128Ser	missense	Exon 25 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.3406A>T	p.Thr1136Ser	missense	Exon 25 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.3394A>T	p.Thr1132Ser	missense	Exon 25 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-98266A>T		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.00502 AC: 559 AN: 111447 Hom.: 6 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.0472

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000715

Gnomad OTH AF: 0.00265

GnomAD2 exomes AF: 0.0116 AC: 2044 AN: 175573 AF XY: 0.0144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000751

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.0332

Gnomad FIN exome AF: 0.0395

Gnomad NFE exome AF: 0.000885

Gnomad OTH exome AF: 0.00644

GnomAD4 exome AF: 0.00623 AC: 6823 AN: 1094585 Hom.: 141 Cov.: 29 AF XY: 0.00796 AC XY: 2868 AN XY: 360407

African (AFR) AF: 0.000190 AC: 5 AN: 26344

American (AMR) AF: 0.0000572 AC: 2 AN: 34959

Ashkenazi Jewish (ASJ) AF: 0.000777 AC: 15 AN: 19298

East Asian (EAS) AF: 0.0698 AC: 2095 AN: 30033

South Asian (SAS) AF: 0.0508 AC: 2702 AN: 53213

European-Finnish (FIN) AF: 0.0387 AC: 1560 AN: 40336

Middle Eastern (MID) AF: 0.00316 AC: 13 AN: 4118

European-Non Finnish (NFE) AF: 0.000227 AC: 191 AN: 840325

Other (OTH) AF: 0.00522 AC: 240 AN: 45959

GnomAD4 genome AF: 0.00503 AC: 561 AN: 111499 Hom.: 6 Cov.: 23 AF XY: 0.00757 AC XY: 255 AN XY: 33699

African (AFR) AF: 0.00 AC: 0 AN: 30698

American (AMR) AF: 0.000191 AC: 2 AN: 10469

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.0360 AC: 127 AN: 3523

South Asian (SAS) AF: 0.0477 AC: 127 AN: 2663

European-Finnish (FIN) AF: 0.0441 AC: 262 AN: 5946

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000715 AC: 38 AN: 53123

Other (OTH) AF: 0.00262 AC: 4 AN: 1529

Alfa AF: 0.00269 Hom.: 19

Bravo AF: 0.00162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.0130 AC: 1577

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	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	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.24
DANN	Benign	0.45
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.14
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.056
Sift	Benign	0.63	T
Sift4G	Benign	0.93	T
Polyphen		0.0010	B
Vest4		0.046
MutPred		0.31		Gain of disorder (P = 0.0598)
MPC		0.016
ClinPred		0.0099	T
GERP RS		-0.42
gMVP		0.057
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: rs3827462; hg19: chrX-32481582; COSMIC: COSV63756966;