6-7558264-G-C

Variant names:

• chr6-7558264-G-C
• rs969373062
• NM_004415.4:c.422G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004415.4(DSP):​c.422G>C​(p.Arg141Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSP NM_004415.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.422G>C	p.Arg141Thr	missense_variant, splice_region_variant	Exon 3 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.422G>C	p.Arg141Thr	missense_variant, splice_region_variant	Exon 3 of 24		NP_001305963.1
DSP	NM_001008844.3	c.422G>C	p.Arg141Thr	missense_variant, splice_region_variant	Exon 3 of 24		NP_001008844.1
DSP	NM_001406591.1	c.422G>C	p.Arg141Thr	missense_variant, splice_region_variant	Exon 3 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.422G>C	p.Arg141Thr	missense_variant, splice_region_variant	Exon 3 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.422G>C	p.Arg141Thr	missense_variant, splice_region_variant	Exon 3 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.422G>C	p.Arg141Thr	missense_variant, splice_region_variant	Exon 3 of 24			ENSP00000518230.1
DSP	ENST00000683563.1	n.314G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 572009). This variant has not been reported in the literature in individuals affected with DSP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 141 of the DSP protein (p.Arg141Thr). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	30
DANN	Benign	0.96
DEOGEN2	Uncertain	0.48	T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.2	D;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.81	P;.
Vest4		0.78
MutPred		0.35		Loss of MoRF binding (P = 0.0219);Loss of MoRF binding (P = 0.0219);
MVP		0.93
MPC		0.58
ClinPred		0.85	D
GERP RS		5.8
Varity_R		0.26
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.83		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs969373062; hg19: chr6-7558497;