rs763523853

Positions:

• chr6-7580356-G-A
• chr6-7580356-G-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.4166G>A​(p.Ser1389Asn) 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 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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, single submitter U:1
• Conservation: PhyloP100: 2.13

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=0.107344866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.4166G>A	p.Ser1389Asn	missense_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.4050+116G>A		intron_variant			NP_001305963.1
DSP	NM_001008844.3	c.3582+584G>A		intron_variant			NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.4166G>A	p.Ser1389Asn	missense_variant	23/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.3582+584G>A		intron_variant		1		ENSP00000396591.2
DSP	ENST00000710359.1	c.4050+116G>A		intron_variant				ENSP00000518230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, University of Leuven

Apr 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-0.76	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.0	N
REVEL	Uncertain	0.36
Sift	Benign	0.32	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.080
MutPred		0.078		Loss of glycosylation at S1389 (P = 0.0394);
MVP		0.60
MPC		0.20
ClinPred		0.19	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.29

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: rs763523853; hg19: chr6-7580589;