6-7571961-A-T

Position:

• chr6-7571961-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004415.4(DSP):​c.2023A>T​(p.Ile675Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.584

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19288075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.2023A>T	p.Ile675Phe	missense_variant	15/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2023A>T	p.Ile675Phe	missense_variant	15/24		NP_001305963.1
DSP	NM_001008844.3	c.2023A>T	p.Ile675Phe	missense_variant	15/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2023A>T	p.Ile675Phe	missense_variant	15/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.2023A>T	p.Ile675Phe	missense_variant	15/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.2023A>T	p.Ile675Phe	missense_variant	15/24			ENSP00000518230	A2
DSP	ENST00000684395.1	n.664A>T		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251238 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 27, 2020

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: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DSP-related conditions. This variant is present in population databases (rs142619902, ExAC 0.001%). This sequence change replaces isoleucine with phenylalanine at codon 675 of the DSP protein (p.Ile675Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 02, 2023

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; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	0.0013	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.73	D;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.91	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Benign	0.29
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.017	D;T
Polyphen		0.023	B;.
Vest4		0.50
MutPred		0.46		Gain of methylation at K674 (P = 0.055);Gain of methylation at K674 (P = 0.055);
MVP		0.87
MPC		0.35
ClinPred		0.20	T
GERP RS		-1.1
Varity_R		0.20
gMVP		0.52

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: rs142619902; hg19: chr6-7572194;