6-7555789-G-T

Variant names:

• chr6-7555789-G-T
• rs140965835
• NM_004415.4:c.242G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_004415.4(DSP):​c.242G>T​(p.Cys81Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C81Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-7555789-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.242G>T	p.Cys81Phe	missense_variant	Exon 2 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.242G>T	p.Cys81Phe	missense_variant	Exon 2 of 24		NP_001305963.1
DSP	NM_001008844.3	c.242G>T	p.Cys81Phe	missense_variant	Exon 2 of 24		NP_001008844.1
DSP	NM_001406591.1	c.242G>T	p.Cys81Phe	missense_variant	Exon 2 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.242G>T	p.Cys81Phe	missense_variant	Exon 2 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Sep 22, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1035519). 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 cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 81 of the DSP protein (p.Cys81Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.69	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.99	D;.
Vest4		0.81
MutPred		0.31		Loss of catalytic residue at L82 (P = 0.0211);Loss of catalytic residue at L82 (P = 0.0211);
MVP		0.85
MPC		1.0
ClinPred		0.89	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
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: rs140965835; hg19: chr6-7556022;