rs34155804

Variant names:

• chrX-32644238-T-A
• rs34155804
• NM_004006.3:c.1225A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-32644238-T-A
• chrX-32644238-T-C

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.1225A>T​(p.Thr409Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,209,415 control chromosomes in the GnomAD database, including 26 homozygotes. There are 610 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T409A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0098 (13 hom., 279 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (13 hom. 331 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0270
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040003657).
• BP6: Variant X-32644238-T-A is Benign according to our data. Variant chrX-32644238-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00981 (1097/111812) while in subpopulation AFR AF = 0.0341 (1048/30729). AF 95% confidence interval is 0.0324. There are 13 homozygotes in GnomAd4. There are 279 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1097 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.1225A>T	p.Thr409Ser	missense	Exon 11 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1213A>T	p.Thr405Ser	missense	Exon 11 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1201A>T	p.Thr401Ser	missense	Exon 11 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.1225A>T	p.Thr409Ser	missense	Exon 11 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1201A>T	p.Thr401Ser	missense	Exon 11 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.247-70392A>T		intron	N/A	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.00982 AC: 1097 AN: 111757 Hom.: 13 Cov.: 23

Gnomad AFR AF: 0.0342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00305

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00597

GnomAD2 exomes AF: 0.00312 AC: 571 AN: 183163 AF XY: 0.00176

Gnomad AFR exome AF: 0.0382

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.00113 AC: 1237 AN: 1097603 Hom.: 13 Cov.: 30 AF XY: 0.000912 AC XY: 331 AN XY: 363035

African (AFR) AF: 0.0365 AC: 964 AN: 26392

American (AMR) AF: 0.00230 AC: 81 AN: 35190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40494

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4135

European-Non Finnish (NFE) AF: 0.0000772 AC: 65 AN: 841616

Other (OTH) AF: 0.00258 AC: 119 AN: 46075

GnomAD4 genome AF: 0.00981 AC: 1097 AN: 111812 Hom.: 13 Cov.: 23 AF XY: 0.00820 AC XY: 279 AN XY: 34006

African (AFR) AF: 0.0341 AC: 1048 AN: 30729

American (AMR) AF: 0.00305 AC: 32 AN: 10496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.000374 AC: 1 AN: 2673

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6133

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

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53160

Other (OTH) AF: 0.00590 AC: 9 AN: 1526

Alfa AF: 0.00181 Hom.: 35

Bravo AF: 0.0122

ESP6500AA AF: 0.0365 AC: 140

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00338 AC: 410

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	Hypertrophic cardiomyopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.98
CADD	Benign	4.8
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.027
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.027
Sift	Benign	0.17	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.46
MPC		0.016
ClinPred		0.0016	T
GERP RS		0.29
gMVP		0.071
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: rs34155804; hg19: chrX-32662355;