X-32565825-G-A

Variant names:

• chrX-32565825-G-A
• rs1800267
• NM_004006.3:c.1869C>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.1869C>T​(p.Leu623Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00615 in 1,209,407 control chromosomes in the GnomAD database, including 282 homozygotes. There are 1,923 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. L623L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.032 (125 hom., 928 hem., cov: 23)
  • Exomes 𝑓: 0.0035 (157 hom. 995 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.630
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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=-0.51).
• BP6: Variant X-32565825-G-A is Benign according to our data. Variant chrX-32565825-G-A is described in ClinVar as Benign. ClinVar VariationId is 94482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 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.1869C>T	p.Leu623Leu	synonymous	Exon 16 of 79	NP_003997.2
	DMD	NM_004009.3		c.1857C>T	p.Leu619Leu	synonymous	Exon 16 of 79	NP_004000.1
	DMD	NM_000109.4		c.1845C>T	p.Leu615Leu	synonymous	Exon 16 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.1869C>T	p.Leu623Leu	synonymous	Exon 16 of 79	ENSP00000354923.3
	DMD	ENST00000288447.9	TSL:1	c.1845C>T	p.Leu615Leu	synonymous	Exon 16 of 18	ENSP00000288447.4
	DMD	ENST00000378677.6	TSL:5	c.1857C>T	p.Leu619Leu	synonymous	Exon 16 of 79	ENSP00000367948.2

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 3590 AN: 111694 Hom.: 125 Cov.: 23

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000734

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000320

Gnomad OTH AF: 0.0293

GnomAD2 exomes AF: 0.00914 AC: 1674 AN: 183164 AF XY: 0.00573

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000269

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00351 AC: 3848 AN: 1097659 Hom.: 157 Cov.: 30 AF XY: 0.00274 AC XY: 995 AN XY: 363055

African (AFR) AF: 0.116 AC: 3050 AN: 26384

American (AMR) AF: 0.00591 AC: 208 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19378

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.000573 AC: 31 AN: 54135

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40517

Middle Eastern (MID) AF: 0.00701 AC: 29 AN: 4135

European-Non Finnish (NFE) AF: 0.000178 AC: 150 AN: 841657

Other (OTH) AF: 0.00825 AC: 380 AN: 46068

GnomAD4 genome AF: 0.0321 AC: 3588 AN: 111748 Hom.: 125 Cov.: 23 AF XY: 0.0273 AC XY: 928 AN XY: 33960

African (AFR) AF: 0.111 AC: 3401 AN: 30735

American (AMR) AF: 0.0119 AC: 125 AN: 10475

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.000368 AC: 1 AN: 2719

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6054

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

European-Non Finnish (NFE) AF: 0.000320 AC: 17 AN: 53152

Other (OTH) AF: 0.0290 AC: 44 AN: 1519

Alfa AF: 0.0127 Hom.: 64

Bravo AF: 0.0373

EpiCase AF: 0.000327

EpiControl AF: 0.000712

ClinVar

ClinVar submissions as Germline

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	-0.51
CADD	Benign	4.3
DANN	Benign	0.73
PhyloP100		0.63
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: rs1800267; hg19: chrX-32583942;