6-7567421-A-G

Position:

• chr6-7567421-A-G

Variant summary

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

The ENST00000379802.8(DSP):​c.1112A>G​(p.His371Arg) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H371L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP ENST00000379802.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.32

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, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.1112A>G	p.His371Arg	missense_variant	9/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1112A>G	p.His371Arg	missense_variant	9/24		NP_001305963.1
DSP	NM_001008844.3	c.1112A>G	p.His371Arg	missense_variant	9/24		NP_001008844.1
DSP	NM_001406591.1	c.1112A>G	p.His371Arg	missense_variant	9/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1112A>G	p.His371Arg	missense_variant	9/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.1112A>G	p.His371Arg	missense_variant	9/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.1112A>G	p.His371Arg	missense_variant	9/24			ENSP00000518230	A2
DSP	ENST00000682228.1	n.436A>G		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 04, 2023

This missense variant replaces histidine with arginine at codon 371 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSP-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 579523). This missense change has been observed in individual(s) with clinical features of DSP-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 371 of the DSP protein (p.His371Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.57		Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);
MVP		0.93
MPC		0.91
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397516912; hg19: chr6-7567654;