rs1317030435

Positions:

• chr6-7579390-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004415.4(DSP):​c.3200C>T​(p.Ala1067Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.86

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06132555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.3200C>T	p.Ala1067Val	missense_variant	23/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.3200C>T	p.Ala1067Val	missense_variant	23/24		NP_001305963.1
DSP	NM_001008844.3	c.3200C>T	p.Ala1067Val	missense_variant	23/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.3200C>T	p.Ala1067Val	missense_variant	23/24	1	NM_004415.4	ENSP00000369129	P2
DSP	ENST00000418664.2	c.3200C>T	p.Ala1067Val	missense_variant	23/24	1		ENSP00000396591	A2
DSP	ENST00000710359.1	c.3200C>T	p.Ala1067Val	missense_variant	23/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 19, 2017

The p.Ala1067Val variant in DSP has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction too ls and conservation analysis suggest that the p.Ala1067Val variant may not impac t the protein, though this information is not predictive enough to rule out path ogenicity. While this variant is located within an exon, computational tools sug gest the creation of a novel splice site; however, this information is not predi ctive enough to determine pathogenicity. In summary, the clinical significance o f the p.Ala1067Val variant is uncertain. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jun 02, 2017

p.Ala1067Val (c.3200C>T) in exon 23 the DSP gene (NM_004415.2; 6:7579623C>T; GRCh37) Given the absent case data on this variant and that rare, missense variation is common in the general population, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Missense variation in DSP must be interpreted with caution. This variant is novel. This variant has not been reported in individuals with cardiomyopathy. Another variant at this position (p.Ala1067Ser) has been reported in ClinVar in one individual with familial hypertrophy cardiomyopathy and is classified as a variant of uncertain significance. Multiple studies have found that rare, missense variation in DSP is common in the general population: According to the ExAC database's constraint data, DSP appears to be fairly tolerant to missense variation (Z=0.91), but not to loss of function/truncating variation (pLI - 1.000). This is supported by literature. In a study examining the genetic underpinnings of ARVC, 16% of 427 controls were found to have missense variants (Kapplinger et al., 2011). Kapplinger and colleagues also proposed that there is a "hot spot" of missense variation in DSP that causes ARVC - from amino acids 250-604. In another study that compared the genetic variation between pooled patients with cardiomyopathy and individuals in the general population via the ExAC database (60,000 control individuals), missense variation in DSP was NOT significantly enriched in cases of DCM or ARVC (Walsh et al., 2016). Another study (Amr et al., 2016) examined the prevalence of genetic variation in cardiomyopathy cases versus controls and determined that missense variation in DSP in general confers a minimal increase in disease risk (OR=0.62). This is in contrast to the high increase in disease risk loss-of-function variation in DSP confers (OR=18.21). Per the test report, "computational prediction tools and conservation analysis suggest that the p.Ala1067Val variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity." The alanine at codon 1067 is not completely conserved across species: elephants, chickens, and other lower vertebrates have other amino acids present at this location. Neighboring amino acids are not completely conserved across species. A nearby variant is reported as pathogenic; however, this is a truncating variant (p.Tyr1065Ter). Loss-of-function variants are a known mechanism of disease in DSP. Furthermore, according to the test report, this variant may introduce a novel splice site: "while this variant is located within an exon, computational tools suggest the creation of a novel splice site; however, this information is not predictive enough to determine pathogenicity." This variant is not present in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 87x in exomes and 34x in genomes. Another variant at this codon, p.Ala1067Ser is present in 1 out of 11,149 individuals of European descent. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.097
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.53	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.27
Sift	Benign	0.66	T;T
Sift4G	Benign	0.87	T;T
Polyphen		0.0	B;.
Vest4		0.085
MutPred		0.081		Gain of methylation at K1064 (P = 0.1057);Gain of methylation at K1064 (P = 0.1057);
MVP		0.54
MPC		0.22
ClinPred		0.50	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1317030435; hg19: chr6-7579623;