rs128626254

chrX-31323625-G-AchrX-31323625-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004006.3(DMD):c.9197C>T(p.Ser3066Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,096,878 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S3066S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.9197C>T	p.Ser3066Leu	missense_variant	62/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.9197C>T	p.Ser3066Leu	missense_variant	62/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 181506 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66032

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096878 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362300

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;.;.;.;.;D;.;D;D;.
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.9	D;.;D;D;D;.;D;.;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;.;D;D;D;.;D;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;D;D;D;.;D;.;.;D
Vest4		0.79, 0.81, 0.84, 0.83, 0.82, 0.78, 0.84, 0.76, 0.81
MutPred		0.62		.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0781);.;
MVP		0.98
MPC		0.038
ClinPred		0.89	D
GERP RS		5.6
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs128626254; hg19: chrX-31341742; COSMIC: COSV58891045;