rs145419141
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2PM5BP4_Strong
The ENST00000357162.7(VPS13B):c.2471C>T(p.Ser824Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S824A) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000357162.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.2471C>T | p.Ser824Phe | missense_variant | 17/62 | ENST00000358544.7 | NP_060360.3 | |
VPS13B | NM_152564.5 | c.2471C>T | p.Ser824Phe | missense_variant | 17/62 | ENST00000357162.7 | NP_689777.3 | |
VPS13B | NM_015243.3 | c.2471C>T | p.Ser824Phe | missense_variant | 17/18 | NP_056058.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.2471C>T | p.Ser824Phe | missense_variant | 17/62 | 1 | NM_017890.5 | ENSP00000351346 | ||
VPS13B | ENST00000357162.7 | c.2471C>T | p.Ser824Phe | missense_variant | 17/62 | 1 | NM_152564.5 | ENSP00000349685 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251200Hom.: 0 AF XY: 0.000169 AC XY: 23AN XY: 135782
GnomAD4 exome AF: 0.000122 AC: 178AN: 1461464Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92AN XY: 727034
GnomAD4 genome AF: 0.000190 AC: 29AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74438
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 30, 2016 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The VPS13B p.Ser824Phe variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs145419141) and ClinVar (classified as a VUS by Invitae, EGL Genetics and Genetic Services Laboratory at the University of Chicago). The variant was also identified in control databases in 42 of 282596 chromosomes at a frequency of 0.000149 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 29 of 129016 chromosomes (freq: 0.000225), Latino in 7 of 35434 chromosomes (freq: 0.000198), South Asian in 5 of 30608 chromosomes (freq: 0.000163) and Other in 1 of 7216 chromosomes (freq: 0.000139), but was not observed in the African, Ashkenazi Jewish, East Asian or European (Finnish) populations. The p.Ser824 residue is not conserved in mammals and four out of five 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. 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2020 | - - |
Cohen syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 05, 2022 | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 824 of the VPS13B protein (p.Ser824Phe). This variant is present in population databases (rs145419141, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 290694). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 16, 2022 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 15, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 30, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 09, 2021 | The c.2471C>T (p.S824F) alteration is located in exon 17 (coding exon 16) of the VPS13B gene. This alteration results from a C to T substitution at nucleotide position 2471, causing the serine (S) at amino acid position 824 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
VPS13B-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 27, 2024 | The VPS13B c.2471C>T variant is predicted to result in the amino acid substitution p.Ser824Phe. This variant was reported in the homozygous state in an individual with late‑onset hemophagocytic lymphohistiocytosis; however, this variant was not considered as the primary cause of disease (Zondag et al. 2022. PubMed ID: 35870028). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Of note, a different variant impacting the same amino acid (p.Ser824Ala) was found in the homozygous state in a patient with a mild version of Cohen syndrome; however, it was reported (phase not indicated) in an unaffected family member (Family AU-17800, Yu et al. 2013. PubMed ID: 23352163). At this time, the clinical significance of the c.2471C>T (p.Ser824Phe) variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at