6-7581163-C-A

Position:

• chr6-7581163-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_004415.4(DSP):​c.4973C>A​(p.Ser1658Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.39

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 3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity DESP_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36987633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.4973C>A	p.Ser1658Tyr	missense_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4050+923C>A		intron_variant			NP_001305963.1
DSP	NM_001008844.3	c.3582+1391C>A		intron_variant			NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.4973C>A	p.Ser1658Tyr	missense_variant	23/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3582+1391C>A		intron_variant		1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4050+923C>A		intron_variant				ENSP00000518230.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.023	D
Polyphen		0.41	B
Vest4		0.45
MutPred		0.24		Loss of phosphorylation at S1658 (P = 0.0459);
MVP		0.50
MPC		0.39
ClinPred		0.21	T
GERP RS		5.9
Varity_R		0.090
gMVP		0.19

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: rs202084959; hg19: chr6-7581396;