rs76440173
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_004733.4(SLC33A1):c.1525G>A(p.Gly509Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00347 in 1,607,140 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0025 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0036 ( 15 hom. )
Consequence
SLC33A1
NM_004733.4 missense
NM_004733.4 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 6.02
Genes affected
SLC33A1 (HGNC:95): (solute carrier family 33 member 1) The protein encoded by this gene is required for the formation of O-acetylated (Ac) gangliosides. The encoded protein is predicted to contain 6 to 10 transmembrane domains, and a leucine zipper motif in transmembrane domain III. Defects in this gene have been reported to cause spastic paraplegia autosomal dominant type 42 (SPG42) in one Chinese family, but not in similar patients of European descent. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.1720002).
BP6
Variant 3-155828335-C-T is Benign according to our data. Variant chr3-155828335-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 343874.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=2}. Variant chr3-155828335-C-T is described in Lovd as [Benign].
BS2
High Homozygotes in GnomAdExome4 at 15 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC33A1 | NM_004733.4 | c.1525G>A | p.Gly509Ser | missense_variant | 6/6 | ENST00000643144.2 | NP_004724.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC33A1 | ENST00000643144.2 | c.1525G>A | p.Gly509Ser | missense_variant | 6/6 | NM_004733.4 | ENSP00000496241 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00252 AC: 383AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00180 AC: 453AN: 251204Hom.: 2 AF XY: 0.00178 AC XY: 242AN XY: 135816
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GnomAD4 exome AF: 0.00357 AC: 5196AN: 1454908Hom.: 15 Cov.: 27 AF XY: 0.00346 AC XY: 2509AN XY: 724304
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GnomAD4 genome AF: 0.00252 AC: 383AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.00251 AC XY: 187AN XY: 74424
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | SLC33A1: BS1, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Dec 29, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2020 | This variant is associated with the following publications: (PMID: 24583203) - |
Spastic paraplegia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 29, 2020 | - - |
Hereditary spastic paraplegia 42 Benign:1
Benign, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 31, 2018 | This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. - |
Hereditary spastic paraplegia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 16, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;H;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;.;D
Sift4G
Uncertain
D;.;D;.;D
Polyphen
D;D;D;.;.
Vest4
MVP
MPC
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