rs41307461
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_033305.3(VPS13A):āc.775A>Gā(p.Asn259Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,613,546 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_033305.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS13A | NM_033305.3 | c.775A>G | p.Asn259Asp | missense_variant | 11/72 | ENST00000360280.8 | |
VPS13A | NM_001018037.2 | c.775A>G | p.Asn259Asp | missense_variant | 11/71 | ||
VPS13A | NM_015186.4 | c.775A>G | p.Asn259Asp | missense_variant | 11/69 | ||
VPS13A | NM_001018038.3 | c.775A>G | p.Asn259Asp | missense_variant | 11/69 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13A | ENST00000360280.8 | c.775A>G | p.Asn259Asp | missense_variant | 11/72 | 1 | NM_033305.3 | P4 | |
VPS13A | ENST00000376636.7 | c.775A>G | p.Asn259Asp | missense_variant | 11/71 | 1 | |||
VPS13A | ENST00000643348.1 | c.775A>G | p.Asn259Asp | missense_variant | 11/69 | ||||
VPS13A | ENST00000645632.1 | c.775A>G | p.Asn259Asp | missense_variant | 11/69 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00249 AC: 379AN: 152050Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00239 AC: 601AN: 251160Hom.: 2 AF XY: 0.00220 AC XY: 299AN XY: 135750
GnomAD4 exome AF: 0.00379 AC: 5535AN: 1461378Hom.: 24 Cov.: 31 AF XY: 0.00358 AC XY: 2600AN XY: 726990
GnomAD4 genome ? AF: 0.00249 AC: 379AN: 152168Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160AN XY: 74394
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:6
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The VPS13A p.Asn259Asp variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs41307461), LOVD 3.0 (classified as likely benign) and in ClinVar (classified as a VUS by Illumina, Athena Diagnostics and Fulgent Genetics and as likely benign by Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen). The variant was also identified in control databases in 705 of 282532 chromosomes (2 homozygous) at a frequency of 0.002495 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 567 of 128988 chromosomes (freq: 0.004396), Ashkenazi Jewish in 41 of 10364 chromosomes (freq: 0.003956), Other in 23 of 7206 chromosomes (freq: 0.003192), European (Finnish) in 37 of 25112 chromosomes (freq: 0.001473), African in 18 of 24922 chromosomes (freq: 0.000722) and Latino in 19 of 35392 chromosomes (freq: 0.000537), but not in the East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asn259 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 14, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2023 | See Variant Classification Assertion Criteria. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | VPS13A: BP4, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Chorea-acanthocytosis Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 29, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
VPS13A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 16, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at