6-7580171-C-G

Position:

• chr6-7580171-C-G

Variant summary

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

The ENST00000379802.8(DSP):​c.3981C>G​(p.Ile1327Met) 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 1,461,802 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 (★). Synonymous variant affecting the same amino acid position (i.e. I1327I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP ENST00000379802.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.60

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=0.19979602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.3981C>G	p.Ile1327Met	missense_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.3981C>G	p.Ile1327Met	missense_variant	23/24		NP_001305963.1
DSP	NM_001008844.3	c.3582+399C>G		intron_variant			NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.3981C>G	p.Ile1327Met	missense_variant	23/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.3582+399C>G		intron_variant		1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.3981C>G	p.Ile1327Met	missense_variant	23/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727192

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces isoleucine with methionine at codon 1327 of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0081	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	6.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.32
Sift	Benign	0.070	T
Sift4G	Uncertain	0.036	D
Polyphen		0.74	P
Vest4		0.38
MutPred		0.20		Loss of catalytic residue at I1327 (P = 0.0948);
MVP		0.78
MPC		0.51
ClinPred		0.30	T
GERP RS		-2.5
Varity_R		0.053
gMVP		0.42

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: rs397516934; hg19: chr6-7580404;