rs1554106845

chr6-7568527-C-T

Variant summary

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

The NM_004415.4(DSP):c.1357C>T(p.Pro453Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P453L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.1357C>T	p.Pro453Ser	missense_variant	11/24	ENST00000379802.8
DSP	NM_001319034.2	c.1357C>T	p.Pro453Ser	missense_variant	11/24
DSP	NM_001008844.3	c.1357C>T	p.Pro453Ser	missense_variant	11/24
DSP	NM_001406591.1	c.1357C>T	p.Pro453Ser	missense_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.1357C>T	p.Pro453Ser	missense_variant	11/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.1357C>T	p.Pro453Ser	missense_variant	11/24	1		A2
DSP	ENST00000710359.1	c.1357C>T	p.Pro453Ser	missense_variant	11/24			A2
DSP	ENST00000682228.1			downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary familial dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Nov 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Uncertain	0.55
Sift	Benign	0.14	T;T
Sift4G	Uncertain	0.011	D;T
Polyphen		1.0	D;.
Vest4		0.60
MutPred		0.29		Gain of phosphorylation at P453 (P = 0.0092);Gain of phosphorylation at P453 (P = 0.0092);
MVP		0.80
MPC		0.83
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.56

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: rs1554106845; hg19: chr6-7568760;