rs375284717
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_015087.5(SPART):āc.560A>Gā(p.Tyr187Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,614,092 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000059 ( 0 hom., cov: 32)
Exomes š: 0.00013 ( 0 hom. )
Consequence
SPART
NM_015087.5 missense
NM_015087.5 missense
Scores
8
7
3
Clinical Significance
Conservation
PhyloP100: 7.26
Genes affected
SPART (HGNC:18514): (spartin) This gene encodes a protein containing a MIT (Microtubule Interacting and Trafficking molecule) domain, and is implicated in regulating endosomal trafficking and mitochondria function. The protein localizes to mitochondria and partially co-localizes with microtubules. Stimulation with epidermal growth factor (EGF) results in protein translocation to the plasma membrane, and the protein functions in the degradation and intracellular trafficking of EGF receptor. Multiple alternatively spliced variants, encoding the same protein, have been identified. Mutations associated with this gene cause autosomal recessive spastic paraplegia 20 (Troyer syndrome). [provided by RefSeq, Nov 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.848
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPART | NM_015087.5 | c.560A>G | p.Tyr187Cys | missense_variant | 2/9 | ENST00000438666.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPART | ENST00000438666.7 | c.560A>G | p.Tyr187Cys | missense_variant | 2/9 | 1 | NM_015087.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152138Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250938Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135610
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GnomAD4 exome AF: 0.000133 AC: 194AN: 1461836Hom.: 0 Cov.: 32 AF XY: 0.000132 AC XY: 96AN XY: 727216
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74460
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2023 | The c.560A>G (p.Y187C) alteration is located in exon 2 (coding exon 1) of the SPG20 gene. This alteration results from a A to G substitution at nucleotide position 560, causing the tyrosine (Y) at amino acid position 187 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 15, 2022 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 187 of the SPART protein (p.Tyr187Cys). This variant is present in population databases (rs375284717, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SPART-related conditions. ClinVar contains an entry for this variant (Variation ID: 409265). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Troyer syndrome Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant classified as Uncertain significance and reported on 08-21-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;D;.;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;.;.
Sift4G
Uncertain
D;D;D;.;D
Polyphen
D;D;D;D;D
Vest4
MVP
MPC
0.46
ClinPred
D
GERP RS
Varity_R
gMVP
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