rs397516943

chr6-7559281-C-Gchr6-7559281-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP3 BP6_Moderate

The NM_004415.4(DSP):c.478C>G(p.Arg160Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.79

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78
• BP6: Variant 6-7559281-C-G is Benign according to our data. Variant chr6-7559281-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2937304.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.478C>G	p.Arg160Gly	missense_variant	4/24	ENST00000379802.8
DSP	NM_001319034.2	c.478C>G	p.Arg160Gly	missense_variant	4/24
DSP	NM_001008844.3	c.478C>G	p.Arg160Gly	missense_variant	4/24
DSP	NM_001406591.1	c.478C>G	p.Arg160Gly	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.478C>G	p.Arg160Gly	missense_variant	4/24	1	NM_004415.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251184 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Mar 13, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	0.0020
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.19	T;T
Polyphen		0.99	D;.
Vest4		0.86
MutPred		0.50		Loss of methylation at R160 (P = 0.0401);Loss of methylation at R160 (P = 0.0401);
MVP		0.96
MPC		0.93
ClinPred		0.69	D
GERP RS		3.8
Varity_R		0.29
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516943; hg19: chr6-7559514; COSMIC: COSV65793658; COSMIC: COSV65793658;