chrX-32468578-G-A

Variant names:

• chrX-32468578-G-A
• rs146384458
• NM_004006.3:c.3082C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BS1 BS2_Supporting

The NM_004006.3(DMD):​c.3082C>T​(p.Arg1028Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000422 in 1,208,686 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1028H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.000036 (0 hom. 16 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.05
• Publications: 2 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14430127).
• BP6: Variant X-32468578-G-A is Benign according to our data. Variant chrX-32468578-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228584.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000108 (12/111490) while in subpopulation SAS AF = 0.00225 (6/2671). AF 95% confidence interval is 0.000978. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 12 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.3082C>T	p.Arg1028Cys	missense	Exon 23 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.3070C>T	p.Arg1024Cys	missense	Exon 23 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.3058C>T	p.Arg1020Cys	missense	Exon 23 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.3082C>T	p.Arg1028Cys	missense	Exon 23 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.3070C>T	p.Arg1024Cys	missense	Exon 23 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-103379C>T		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.000108 AC: 12 AN: 111441 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000385 AC: 7 AN: 181642 AF XY: 0.0000601

Gnomad AFR exome AF: 0.000229

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: 0.000223

GnomAD4 exome AF: 0.0000355 AC: 39 AN: 1097196 Hom.: 0 Cov.: 30 AF XY: 0.0000441 AC XY: 16 AN XY: 362752

African (AFR) AF: 0.0000379 AC: 1 AN: 26384

American (AMR) AF: 0.00 AC: 0 AN: 35134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.0000995 AC: 3 AN: 30143

South Asian (SAS) AF: 0.000499 AC: 27 AN: 54065

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40477

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841463

Other (OTH) AF: 0.0000869 AC: 4 AN: 46033

GnomAD4 genome AF: 0.000108 AC: 12 AN: 111490 Hom.: 0 Cov.: 22 AF XY: 0.000148 AC XY: 5 AN XY: 33696

African (AFR) AF: 0.000195 AC: 6 AN: 30714

American (AMR) AF: 0.00 AC: 0 AN: 10414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3543

South Asian (SAS) AF: 0.00225 AC: 6 AN: 2671

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6003

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53098

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.000783 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	-	1	Duchenne muscular dystrophy (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.67	T
PhyloP100		4.0
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.34
MVP		0.70
MPC		0.017
ClinPred		0.21	T
GERP RS		4.2
gMVP		0.33
Mutation Taster		=100/0	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: rs146384458; hg19: chrX-32486695;