22-32043315-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_000343.4(SLC5A1):​c.34G>A​(p.Ala12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A12V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

SLC5A1
NM_000343.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -2.95
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 Likely_benign. Variant got -1 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.04139352).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC5A1NM_000343.4 linkuse as main transcriptc.34G>A p.Ala12Thr missense_variant 1/15 ENST00000266088.9
SLC5A1XM_011530331.2 linkuse as main transcriptc.34G>A p.Ala12Thr missense_variant 1/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC5A1ENST00000266088.9 linkuse as main transcriptc.34G>A p.Ala12Thr missense_variant 1/151 NM_000343.4 P1P13866-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000478
AC:
12
AN:
250806
Hom.:
0
AF XY:
0.0000664
AC XY:
9
AN XY:
135644
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:
0.0000970
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000506
AC:
74
AN:
1461814
Hom.:
0
Cov.:
31
AF XY:
0.0000468
AC XY:
34
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000621
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.000109
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 12, 2021The c.34G>A (p.A12T) alteration is located in exon 1 (coding exon 1) of the SLC5A1 gene. This alteration results from a G to A substitution at nucleotide position 34, causing the alanine (A) at amino acid position 12 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Congenital glucose-galactose malabsorption Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 19, 2022This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 12 of the SLC5A1 protein (p.Ala12Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SLC5A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1005551). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.062
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
0.023
DANN
Benign
0.83
DEOGEN2
Benign
0.043
T
Eigen
Benign
-2.1
Eigen_PC
Benign
-2.2
FATHMM_MKL
Benign
0.017
N
LIST_S2
Benign
0.31
T
M_CAP
Uncertain
0.090
D
MetaRNN
Benign
0.041
T
MetaSVM
Benign
-0.71
T
MutationAssessor
Benign
-0.61
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.29
N
REVEL
Benign
0.28
Sift
Benign
0.22
T
Sift4G
Benign
0.64
T
Polyphen
0.0
B
Vest4
0.070
MutPred
0.21
Gain of glycosylation at A12 (P = 0.0312);
MVP
0.47
MPC
0.45
ClinPred
0.11
T
GERP RS
-9.1
Varity_R
0.029
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs202189110; hg19: chr22-32439302; COSMIC: COSV56684996; COSMIC: COSV56684996; API