NM_004415.4:c.1352G>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_004415.4(DSP):​c.1352G>A​(p.Arg451His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• 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, 0.825
• PP5: Variant 6-7568522-G-A is Pathogenic according to our data. Variant chr6-7568522-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188459.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1352G>A	p.Arg451His	missense_variant	Exon 11 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1352G>A	p.Arg451His	missense_variant	Exon 11 of 24		NP_001305963.1
DSP	NM_001008844.3	c.1352G>A	p.Arg451His	missense_variant	Exon 11 of 24		NP_001008844.1
DSP	NM_001406591.1	c.1352G>A	p.Arg451His	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>A	p.Arg451His	missense_variant	Exon 11 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1352G>A	p.Arg451His	missense_variant	Exon 11 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1352G>A	p.Arg451His	missense_variant	Exon 11 of 24			ENSP00000518230.1
DSP	ENST00000682228.1	n.*29G>A		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 451 of the DSP protein (p.Arg451His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257, 33460606; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188459). 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. This variant disrupts the p.Arg451 amino acid residue in DSP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31194698). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Nov 20, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34352074, 31402444, 33460606, 36175056, 27532257) -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Uncertain:1

Feb 24, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.46		Loss of MoRF binding (P = 0.0123);Loss of MoRF binding (P = 0.0123);
MVP		0.89
MPC		0.92
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.82

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; COSMIC: COSV65794210; COSMIC: COSV65794210;