chr6-7568522-G-T

Variant names:

• chr6-7568522-G-T
• rs786204294
• NM_004415.4:c.1352G>T

Variant summary

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

The NM_004415.4(DSP):​c.1352G>T​(p.Arg451Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1352G>T	p.Arg451Leu	missense_variant	Exon 11 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1352G>T	p.Arg451Leu	missense_variant	Exon 11 of 24		NP_001305963.1
DSP	NM_001008844.3	c.1352G>T	p.Arg451Leu	missense_variant	Exon 11 of 24		NP_001008844.1
DSP	NM_001406591.1	c.1352G>T	p.Arg451Leu	missense_variant	Exon 11 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1352G>T	p.Arg451Leu	missense_variant	Exon 11 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1352G>T	p.Arg451Leu	missense_variant	Exon 11 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1352G>T	p.Arg451Leu	missense_variant	Exon 11 of 24			ENSP00000518230.1
DSP	ENST00000682228.1	n.*29G>T		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Keratosis palmoplantaris striata 2 Uncertain:1

Apr 01, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.88
MutPred		0.48		Loss of MoRF binding (P = 0.0114);Loss of MoRF binding (P = 0.0114);
MVP		0.91
MPC		0.92
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.80
gMVP		0.85

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: rs786204294; hg19: chr6-7568755;