chr22-32104793-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_000343.4(SLC5A1):c.1673G>A(p.Arg558His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,610 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
SLC5A1
NM_000343.4 missense
NM_000343.4 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 9.19
Genes affected
SLC5A1 (HGNC:11036): (solute carrier family 5 member 1) This gene encodes a member of the sodium-dependent glucose transporter (SGLT) family. The encoded integral membrane protein is the primary mediator of dietary glucose and galactose uptake from the intestinal lumen. Mutations in this gene have been associated with glucose-galactose malabsorption. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SLC5A1. . Gene score misZ 1.833 (greater than the threshold 3.09). Trascript score misZ 3.1348 (greater than threshold 3.09). GenCC has associacion of gene with glucose-galactose malabsorption.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.934
PP5
Variant 22-32104793-G-A is Pathogenic according to our data. Variant chr22-32104793-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127077.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC5A1 | NM_000343.4 | c.1673G>A | p.Arg558His | missense_variant | 14/15 | ENST00000266088.9 | NP_000334.1 | |
SLC5A1 | NM_001256314.2 | c.1292G>A | p.Arg431His | missense_variant | 13/14 | NP_001243243.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC5A1 | ENST00000266088.9 | c.1673G>A | p.Arg558His | missense_variant | 14/15 | 1 | NM_000343.4 | ENSP00000266088 | P1 | |
SLC5A1 | ENST00000543737.2 | c.1292G>A | p.Arg431His | missense_variant | 13/14 | 2 | ENSP00000444898 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152052Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251244Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135774
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461558Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 727090
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152052Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74252
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Congenital glucose-galactose malabsorption Pathogenic:2Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 558 of the SLC5A1 protein (p.Arg558His). This variant is present in population databases (rs201799893, gnomAD 0.02%). This missense change has been observed in individual(s) with glucose-galactose malabsorption (PMID: 20486940). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127077). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC5A1 protein function. This variant disrupts the p.Arg558 amino acid residue in SLC5A1. Other variant(s) that disrupt this residue have been observed in individuals with SLC5A1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 04, 2022 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 09, 2016 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Benign
T;T
Sift4G
Uncertain
D;T
Polyphen
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