chrX-32463590-A-G

Variant names:

• chrX-32463590-A-G
• rs876657778
• NM_004006.3:c.3281T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_Moderate BS2_Supporting

The NM_004006.3(DMD):​c.3281T>C​(p.Leu1094Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,135,330 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L1094L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000059 (0 hom. 3 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 9.10
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865
• BS2: High AC in GnomAd4 at 9 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3281T>C	p.Leu1094Ser	missense	Exon 25 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.3269T>C	p.Leu1090Ser	missense	Exon 25 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.3257T>C	p.Leu1086Ser	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.3281T>C	p.Leu1094Ser	missense	Exon 25 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.3269T>C	p.Leu1090Ser	missense	Exon 25 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-98391T>C		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.0000802 AC: 9 AN: 112211 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000877 AC: 1 AN: 114010 AF XY: 0.00

Gnomad AFR exome AF: 0.000110

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000586 AC: 6 AN: 1023119 Hom.: 0 Cov.: 27 AF XY: 0.00000967 AC XY: 3 AN XY: 310103

African (AFR) AF: 0.000164 AC: 4 AN: 24393

American (AMR) AF: 0.00 AC: 0 AN: 27025

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17463

East Asian (EAS) AF: 0.00 AC: 0 AN: 27554

South Asian (SAS) AF: 0.00 AC: 0 AN: 41070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3888

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 801621

Other (OTH) AF: 0.0000466 AC: 2 AN: 42897

GnomAD4 genome AF: 0.0000802 AC: 9 AN: 112211 Hom.: 0 Cov.: 23 AF XY: 0.0000291 AC XY: 1 AN XY: 34365

African (AFR) AF: 0.000259 AC: 8 AN: 30858

American (AMR) AF: 0.0000947 AC: 1 AN: 10563

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53277

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Duchenne muscular dystrophy (1)
-	1	-	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	1	-	Intellectual disability (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.44	T
PhyloP100		9.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.67		Gain of disorder (P = 0.0151)
MVP		0.93
MPC		0.13
ClinPred		0.55	D
GERP RS		5.4
gMVP		0.47
Mutation Taster		=94/6	polymorphism

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: rs876657778; hg19: chrX-32481707;