6-7574089-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_004415.4(DSP):c.2134G>A(p.Val712Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V712L) has been classified as Uncertain significance.
Frequency
Consequence
NM_004415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.2134G>A | p.Val712Met | missense_variant | 16/24 | ENST00000379802.8 | |
DSP | NM_001319034.2 | c.2134G>A | p.Val712Met | missense_variant | 16/24 | ||
DSP | NM_001008844.3 | c.2134G>A | p.Val712Met | missense_variant | 16/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.2134G>A | p.Val712Met | missense_variant | 16/24 | 1 | NM_004415.4 | P2 | |
DSP | ENST00000418664.2 | c.2134G>A | p.Val712Met | missense_variant | 16/24 | 1 | A2 | ||
DSP | ENST00000710359.1 | c.2134G>A | p.Val712Met | missense_variant | 16/24 | A2 | |||
DSP | ENST00000684395.1 | n.775G>A | non_coding_transcript_exon_variant | 3/5 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251274Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135812
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461758Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727172
GnomAD4 genome AF: 0.000105 AC: 16AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74380
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 15, 2012 | The Val712Met variant in DSP has not been reported in the literature nor previou sly identified by our laboratory. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is need ed to fully assess the clinical significance of the Val712Met variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 05, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 23, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 24, 2021 | The c.2134G>A (p.V712M) alteration is located in exon 16 (coding exon 16) of the DSP gene. This alteration results from a G to A substitution at nucleotide position 2134, causing the valine (V) at amino acid position 712 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
DSP-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 17, 2022 | The DSP c.2134G>A variant is predicted to result in the amino acid substitution p.Val712Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-7574322-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | DSP NM_004415.3 exon 16 p.Val712Met (c.2134G>A): This variant has not been reported in the literature and is present in 0.02% (6/24970) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/6-7574322-G-A). This variant is present in ClinVar (Variation ID:44871). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at