rs1060500619

Positions:

• chr6-7580089-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_004415.4(DSP):​c.3899A>G​(p.Gln1300Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. Q1300E) 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: 4.26

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31374925).
• BP6: Variant 6-7580089-A-G is Benign according to our data. Variant chr6-7580089-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 405249.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.3899A>G	p.Gln1300Arg	missense_variant	23/24	ENST00000379802.8
DSP	NM_001319034.2	c.3899A>G	p.Gln1300Arg	missense_variant	23/24
DSP	NM_001008844.3	c.3582+317A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.3899A>G	p.Gln1300Arg	missense_variant	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3582+317A>G		intron_variant		1		A2
DSP	ENST00000710359.1	c.3899A>G	p.Gln1300Arg	missense_variant	23/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250878 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135696

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

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

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

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

Dec 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.0029	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.81
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.014
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.33	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.16	N
REVEL	Uncertain	0.37
Sift	Benign	0.41	T
Sift4G	Benign	0.71	T
Polyphen		0.81	P
Vest4		0.59
MutPred		0.063		Gain of MoRF binding (P = 0.018);
MVP		0.78
MPC		0.28
ClinPred		0.18	T
GERP RS		5.2
Varity_R		0.061
gMVP		0.40

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: rs1060500619; hg19: chr6-7580322;