rs771948271

Positions:

• chr6-7579513-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP6

The NM_004415.4(DSP):​c.3323A>G​(p.Asn1108Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,724 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.21

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3528251).
• BP6: Variant 6-7579513-A-G is Benign according to our data. Variant chr6-7579513-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 534310.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.3323A>G	p.Asn1108Ser	missense_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.3323A>G	p.Asn1108Ser	missense_variant	23/24		NP_001305963.1
DSP	NM_001008844.3	c.3323A>G	p.Asn1108Ser	missense_variant	23/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.3323A>G	p.Asn1108Ser	missense_variant	23/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.3323A>G	p.Asn1108Ser	missense_variant	23/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.3323A>G	p.Asn1108Ser	missense_variant	23/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250398 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135560

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461724 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2021

The p.N1108S variant (also known as c.3323A>G), located in coding exon 23 of the DSP gene, results from an A to G substitution at nucleotide position 3323. The asparagine at codon 1108 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.51	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.29
Sift	Benign	0.65	T;T
Sift4G	Benign	0.78	T;T
Polyphen		1.0	D;.
Vest4		0.60
MutPred		0.12		Gain of phosphorylation at N1108 (P = 0.0539);Gain of phosphorylation at N1108 (P = 0.0539);
MVP		0.84
MPC		0.72
ClinPred		0.25	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.15

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: rs771948271; hg19: chr6-7579746;