X-32365167-C-A

Variant names:

• chrX-32365167-C-A
• rs61733574
• NM_004006.3:c.4878G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004006.3(DMD):​c.4878G>T​(p.Val1626Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,208,825 control chromosomes in the GnomAD database, including 97 homozygotes. There are 1,326 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1626V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (55 hom., 607 hem., cov: 22)
  • Exomes 𝑓: 0.0023 (42 hom. 719 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.00
• Publications: 1 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=-0.68).
• BP6: Variant X-32365167-C-A is Benign according to our data. Variant chrX-32365167-C-A is described in ClinVar as Benign. ClinVar VariationId is 94642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0646 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.4878G>T	p.Val1626Val	synonymous	Exon 35 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.4866G>T	p.Val1622Val	synonymous	Exon 35 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.4854G>T	p.Val1618Val	synonymous	Exon 35 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.4878G>T	p.Val1626Val	synonymous	Exon 35 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.4866G>T	p.Val1622Val	synonymous	Exon 35 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.846G>T	p.Val282Val	synonymous	Exon 7 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 2202 AN: 111085 Hom.: 54 Cov.: 22

Gnomad AFR AF: 0.0666

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00265

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000415

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00604 AC: 1106 AN: 183052 AF XY: 0.00433

Gnomad AFR exome AF: 0.0705

Gnomad AMR exome AF: 0.00453

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00229 AC: 2517 AN: 1097692 Hom.: 42 Cov.: 30 AF XY: 0.00198 AC XY: 719 AN XY: 363206

African (AFR) AF: 0.0683 AC: 1802 AN: 26379

American (AMR) AF: 0.00534 AC: 188 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30171

South Asian (SAS) AF: 0.00103 AC: 56 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40476

Middle Eastern (MID) AF: 0.00435 AC: 18 AN: 4134

European-Non Finnish (NFE) AF: 0.000233 AC: 196 AN: 841788

Other (OTH) AF: 0.00558 AC: 257 AN: 46060

GnomAD4 genome AF: 0.0199 AC: 2215 AN: 111133 Hom.: 55 Cov.: 22 AF XY: 0.0182 AC XY: 607 AN XY: 33361

African (AFR) AF: 0.0670 AC: 2052 AN: 30632

American (AMR) AF: 0.0106 AC: 110 AN: 10343

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3512

South Asian (SAS) AF: 0.00190 AC: 5 AN: 2633

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5898

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.000415 AC: 22 AN: 53059

Other (OTH) AF: 0.0165 AC: 25 AN: 1511

Alfa AF: 0.00572 Hom.: 18

Bravo AF: 0.0225

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	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	-0.68
CADD	Benign	5.8
DANN	Benign	0.72
PhyloP100		0.0
Mutation Taster		=99/1	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: rs61733574; hg19: chrX-32383284;