chr6-7565470-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1PP3BP6
The NM_004415.4(DSP):c.889G>A(p.Asp297Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00018 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense
NM_004415.4 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 9.86
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
In a repeat Spectrin 2 (size 103) in uniprot entity DESP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004415.4
PP3
MetaRNN computational evidence supports a deleterious effect, 0.787
BP6
Variant 6-7565470-G-A is Benign according to our data. Variant chr6-7565470-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44980.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=8}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DSP | NM_004415.4 | c.889G>A | p.Asp297Asn | missense_variant | 7/24 | ENST00000379802.8 | NP_004406.2 | |
| DSP | NM_001319034.2 | c.889G>A | p.Asp297Asn | missense_variant | 7/24 | NP_001305963.1 | ||
| DSP | NM_001008844.3 | c.889G>A | p.Asp297Asn | missense_variant | 7/24 | NP_001008844.1 | ||
| DSP | NM_001406591.1 | c.889G>A | p.Asp297Asn | missense_variant | 7/11 | NP_001393520.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DSP | ENST00000379802.8 | c.889G>A | p.Asp297Asn | missense_variant | 7/24 | 1 | NM_004415.4 | ENSP00000369129.3 |
Frequencies
GnomAD3 genomes 0.000125 AC: 19AN: 152138Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251334Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135834
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GnomAD4 exome AF: 0.000179 AC: 261AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.000177 AC XY: 129AN XY: 727216
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GnomAD4 genome 0.000125 AC: 19AN: 152138Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6AN XY: 74308
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Oct 24, 2016 | p.Asp297Asn (c.889G>A) in the DSP gene (NM_004415.2) Seen in a patient with unexplained cardiac arrest and family history of sudden death and early-onset atrial fibrillation. Testing done by Invitae. Given its presence in controls and lack of case data, 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"). Per our searches and the lab report, there is no case data available for this variant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The aspartic acid at codon 297 is conserved across species. This variant is present in 10 of 60,683 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 2016). Specifically this variant was observed in 8 of 33340 individuals of European (non-Finnish) descent, 1 of 5202 individuals of African descent and 1 of 454 individuals of “other†descent. Of note, Kapplinger et al. (2011) from Michael Ackerman’s group have reported a significant yield of rare missense variants in the ARVC genes of presumably healthy controls from various ethnicities. According to their data, 16% of 427 controls hosted missense variants—similar to the 21% yield in 175 Dutch and U.S. ARVC cases. This is a reminder that missense variants of unknown significance in ARVC-related genes need to be interpreted with caution. Kapplinger et al. also report a “hot spot†for DSP variants between amino acids 250-604 in patients with ARVC but not in controls. Furthermore, in the ExAC constraint analyses, DSP appears to be fairly tolerant to missense variation (Z=0.91), but not to loss of function/truncating variation (pLI=1.000) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 21, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 08, 2021 | Reported in a patient with ARVC/D who also harbored a pathogenic variant in the PKP2 gene (Tan et al., 2010); Also reported in a patient with dilated cardiomyopathy; however, this variant was also reported in two control individuals from this study (Mazzarotto et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 44980; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31983221, 20857253) - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2012 | The Asp297Asn variant (DSP) has been identified in 1/7020 European American chro mosomes and 1/3738 African American chromosomes from a broad population by the N HLBI Exome sequencing project (http://evs.gs.washington.edu/EVS). Aspartic acid (Asp) at position 297 is highly conserved in mammals and across evolutionarily d istant species, though computational analyses (biochemical amino acid properties , AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against a n impact to the protein. Additional information is needed to fully assess the cl inical significance of the Asp297Asn variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 11, 2021 | Variant summary: DSP c.889G>A (p.Asp297Asn) results in a conservative amino acid change located in the Spectrin/alpha-actinin repeat (IPR018159) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251334 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (6e-05 vs 0.0002), allowing no conclusion about variant significance. c.889G>A has been reported in the literature in an individual affected with Dilated cardiomyopathy but it was also reported in healthy controls (Mazzarotto_2020). This report does not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiomyopathy Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jan 05, 2024 | This sequence change in DSP is predicted to replace aspartic acid with asparagine at codon 297, p.(Asp297Asn). The aspartic acid residue is highly conserved (100 vertebrates, UCSC) and is located in the globular 1 region. There is a small physicochemical difference between aspartic acid and asparagine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.012% (16/129,034 alleles) in the European (non-Finnish) population. This variant has been reported in multiple individuals with and without cardiomyopathy. (PMID: 31983221, 33874732). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.731). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 18, 2023 | This missense variant replaces aspartic acid with asparagine at codon 297 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 20/282706 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Conduction disorder of the heart Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Apr 16, 2019 | - - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 24, 2022 | The c.889G>A (p.D297N) alteration is located in exon 7 (coding exon 7) of the DSP gene. This alteration results from a G to A substitution at nucleotide position 889, causing the aspartic acid (D) at amino acid position 297 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
DSP-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 28, 2024 | The DSP c.889G>A variant is predicted to result in the amino acid substitution p.Asp297Asn. This variant has been reported in a cohort studies of dilated cardiomyopathy (Table S3, Mazzarotto et al. 2020. PubMed ID: 31983221; Table S9, McGurk et al. 2023. PubMed ID: 37652022). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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 | Jan 02, 2024 | - - |
Lethal acantholytic epidermolysis bullosa Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Woolly hair-skin fragility syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Arrhythmogenic right ventricular dysplasia 8 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
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gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at