rs168745
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1
The NM_018206.6(VPS35):c.1938C>T(p.His646=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,614,194 control chromosomes in the GnomAD database, including 800,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.98 ( 72733 hom., cov: 32)
Exomes 𝑓: 1.0 ( 727643 hom. )
Consequence
VPS35
NM_018206.6 synonymous
NM_018206.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.341
Genes affected
VPS35 (HGNC:13487): (VPS35 retromer complex component) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -15 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.49).
BP6
?
Variant 16-46662372-G-A is Benign according to our data. Variant chr16-46662372-G-A is described in ClinVar as [Benign]. Clinvar id is 1166780.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-46662372-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.341 with no splicing effect.
BA1
?
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VPS35 | NM_018206.6 | c.1938C>T | p.His646= | synonymous_variant | 15/17 | ENST00000299138.12 | |
VPS35 | XM_011523227.4 | c.1851C>T | p.His617= | synonymous_variant | 15/17 | ||
VPS35 | XM_005256045.4 | c.1737C>T | p.His579= | synonymous_variant | 13/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS35 | ENST00000299138.12 | c.1938C>T | p.His646= | synonymous_variant | 15/17 | 1 | NM_018206.6 | P1 | |
VPS35 | ENST00000568784.6 | c.*2608C>T | 3_prime_UTR_variant, NMD_transcript_variant | 15/17 | 1 | ||||
VPS35 | ENST00000562420.1 | n.576C>T | non_coding_transcript_exon_variant | 3/4 | 2 | ||||
VPS35 | ENST00000647959.1 | c.*2001C>T | 3_prime_UTR_variant, NMD_transcript_variant | 16/18 |
Frequencies
GnomAD3 genomes ? AF: 0.977 AC: 148661AN: 152186Hom.: 72688 Cov.: 32
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GnomAD3 exomes AF: 0.994 AC: 249749AN: 251282Hom.: 124151 AF XY: 0.996 AC XY: 135216AN XY: 135796
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GnomAD4 exome AF: 0.998 AC: 1458489AN: 1461890Hom.: 727643 Cov.: 76 AF XY: 0.998 AC XY: 725836AN XY: 727244
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GnomAD4 genome ? AF: 0.977 AC: 148763AN: 152304Hom.: 72733 Cov.: 32 AF XY: 0.977 AC XY: 72764AN XY: 74478
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Parkinson disease 17 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
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DANN
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RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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