chr22-32043364-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000343.4(SLC5A1):ā€‹c.83A>Gā€‹(p.Asp28Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,068 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˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

SLC5A1
NM_000343.4 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 4.68
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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, 0.915

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC5A1NM_000343.4 linkuse as main transcriptc.83A>G p.Asp28Gly missense_variant 1/15 ENST00000266088.9 NP_000334.1
SLC5A1XM_011530331.2 linkuse as main transcriptc.83A>G p.Asp28Gly missense_variant 1/12 XP_011528633.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC5A1ENST00000266088.9 linkuse as main transcriptc.83A>G p.Asp28Gly missense_variant 1/151 NM_000343.4 ENSP00000266088 P1P13866-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250826
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135642
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461868
Hom.:
0
Cov.:
32
AF XY:
0.00000825
AC XY:
6
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital glucose-galactose malabsorption Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 16, 2021This sequence change replaces aspartic acid with glycine at codon 28 of the SLC5A1 protein (p.Asp28Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs121912669, ExAC 0.006%). This missense change has been observed in individuals with glucose-galactose malabsorption (PMID: 8563765, 17903058). ClinVar contains an entry for this variant (Variation ID: 12908). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Asp28 amino acid residue in SLC5A1. Other variant(s) that disrupt this residue have been observed in individuals with SLC5A1-related conditions (PMID: 2008213), which suggests that this may be a clinically significant amino acid residue. 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. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 19, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
3.9
H
MutationTaster
Benign
1.0
A
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-6.0
D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.78
MutPred
0.72
Gain of catalytic residue at S30 (P = 0.0438);
MVP
0.96
MPC
1.2
ClinPred
1.0
D
GERP RS
4.8
Varity_R
0.80
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121912669; hg19: chr22-32439351; API