rs143628111

Variant names:

• chrX-32448537-G-A
• rs143628111
• NM_004006.3:c.3705C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004006.3(DMD):​c.3705C>T​(p.Ala1235Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,206,657 control chromosomes in the GnomAD database, including 53 homozygotes. There are 838 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., 400 hem., cov: 23)
  • Exomes 𝑓: 0.0015 (29 hom. 438 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.33
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-32448537-G-A is Benign according to our data. Variant chrX-32448537-G-A is described in ClinVar as Benign. ClinVar VariationId is 94603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0141 (1567/110970) while in subpopulation AFR AF = 0.049 (1503/30671). AF 95% confidence interval is 0.0469. There are 24 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1567 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.3705C>T	p.Ala1235Ala	synonymous	Exon 27 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.3693C>T	p.Ala1231Ala	synonymous	Exon 27 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.3681C>T	p.Ala1227Ala	synonymous	Exon 27 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.3705C>T	p.Ala1235Ala	synonymous	Exon 27 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.3693C>T	p.Ala1231Ala	synonymous	Exon 27 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-83338C>T		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 1565 AN: 110920 Hom.: 24 Cov.: 23

Gnomad AFR AF: 0.0490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000761

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00407 AC: 743 AN: 182414 AF XY: 0.00250

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00178

GnomAD4 exome AF: 0.00149 AC: 1629 AN: 1095687 Hom.: 29 Cov.: 30 AF XY: 0.00121 AC XY: 438 AN XY: 362235

African (AFR) AF: 0.0517 AC: 1357 AN: 26247

American (AMR) AF: 0.00318 AC: 112 AN: 35168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19283

East Asian (EAS) AF: 0.00 AC: 0 AN: 30120

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40492

Middle Eastern (MID) AF: 0.00170 AC: 7 AN: 4120

European-Non Finnish (NFE) AF: 0.0000238 AC: 20 AN: 840236

Other (OTH) AF: 0.00285 AC: 131 AN: 45935

GnomAD4 genome AF: 0.0141 AC: 1567 AN: 110970 Hom.: 24 Cov.: 23 AF XY: 0.0119 AC XY: 400 AN XY: 33602

African (AFR) AF: 0.0490 AC: 1503 AN: 30671

American (AMR) AF: 0.00431 AC: 45 AN: 10432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2607

East Asian (EAS) AF: 0.00 AC: 0 AN: 3511

South Asian (SAS) AF: 0.00 AC: 0 AN: 2708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000761 AC: 4 AN: 52554

Other (OTH) AF: 0.00995 AC: 15 AN: 1508

Alfa AF: 0.00729 Hom.: 42

Bravo AF: 0.0162

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.3
DANN	Benign	0.63
PhyloP100		1.3
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: rs143628111; hg19: chrX-32466654;