rs17683430

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_000343.4(SLC5A1):​c.1231G>A​(p.Ala411Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0656 in 1,613,408 control chromosomes in the GnomAD database, including 3,945 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 207 hom., cov: 32)
Exomes 𝑓: 0.068 ( 3738 hom. )

Consequence

SLC5A1
NM_000343.4 missense

Scores

1
17

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.30
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 Benign. Variant got -17 ACMG points.

PM1
In a disulfide_bond (size 256) in uniprot entity SC5A1_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000343.4
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=0.00344944).
BP6
Variant 22-32091713-G-A is Benign according to our data. Variant chr22-32091713-G-A is described in ClinVar as [Benign]. Clinvar id is 341252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC5A1NM_000343.4 linkuse as main transcriptc.1231G>A p.Ala411Thr missense_variant 11/15 ENST00000266088.9 NP_000334.1 P13866-1
SLC5A1NM_001256314.2 linkuse as main transcriptc.850G>A p.Ala284Thr missense_variant 10/14 NP_001243243.1 P13866-2
SLC5A1XM_011530331.2 linkuse as main transcriptc.1231G>A p.Ala411Thr missense_variant 11/12 XP_011528633.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC5A1ENST00000266088.9 linkuse as main transcriptc.1231G>A p.Ala411Thr missense_variant 11/151 NM_000343.4 ENSP00000266088.4 P13866-1
SLC5A1ENST00000543737.2 linkuse as main transcriptc.850G>A p.Ala284Thr missense_variant 10/142 ENSP00000444898.1 P13866-2
SLC5A1ENST00000477969.1 linkuse as main transcriptn.397G>A non_coding_transcript_exon_variant 3/53

Frequencies

GnomAD3 genomes
AF:
0.0450
AC:
6840
AN:
151950
Hom.:
208
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0124
Gnomad AMI
AF:
0.00659
Gnomad AMR
AF:
0.0341
Gnomad ASJ
AF:
0.0412
Gnomad EAS
AF:
0.00116
Gnomad SAS
AF:
0.0374
Gnomad FIN
AF:
0.0559
Gnomad MID
AF:
0.0316
Gnomad NFE
AF:
0.0705
Gnomad OTH
AF:
0.0369
GnomAD3 exomes
AF:
0.0486
AC:
12204
AN:
251274
Hom.:
388
AF XY:
0.0496
AC XY:
6731
AN XY:
135784
show subpopulations
Gnomad AFR exome
AF:
0.0115
Gnomad AMR exome
AF:
0.0291
Gnomad ASJ exome
AF:
0.0382
Gnomad EAS exome
AF:
0.00131
Gnomad SAS exome
AF:
0.0391
Gnomad FIN exome
AF:
0.0517
Gnomad NFE exome
AF:
0.0705
Gnomad OTH exome
AF:
0.0455
GnomAD4 exome
AF:
0.0678
AC:
99022
AN:
1461340
Hom.:
3738
Cov.:
31
AF XY:
0.0670
AC XY:
48693
AN XY:
727002
show subpopulations
Gnomad4 AFR exome
AF:
0.00995
Gnomad4 AMR exome
AF:
0.0318
Gnomad4 ASJ exome
AF:
0.0408
Gnomad4 EAS exome
AF:
0.00186
Gnomad4 SAS exome
AF:
0.0425
Gnomad4 FIN exome
AF:
0.0565
Gnomad4 NFE exome
AF:
0.0772
Gnomad4 OTH exome
AF:
0.0581
GnomAD4 genome
AF:
0.0450
AC:
6841
AN:
152068
Hom.:
207
Cov.:
32
AF XY:
0.0435
AC XY:
3229
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.0123
Gnomad4 AMR
AF:
0.0344
Gnomad4 ASJ
AF:
0.0412
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.0379
Gnomad4 FIN
AF:
0.0559
Gnomad4 NFE
AF:
0.0705
Gnomad4 OTH
AF:
0.0365
Alfa
AF:
0.0603
Hom.:
505
Bravo
AF:
0.0427
TwinsUK
AF:
0.0747
AC:
277
ALSPAC
AF:
0.0791
AC:
305
ESP6500AA
AF:
0.0138
AC:
61
ESP6500EA
AF:
0.0700
AC:
602
ExAC
AF:
0.0501
AC:
6079
Asia WGS
AF:
0.0200
AC:
70
AN:
3478
EpiCase
AF:
0.0603
EpiControl
AF:
0.0660

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Congenital glucose-galactose malabsorption Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 28, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
16
DANN
Benign
0.21
DEOGEN2
Benign
0.047
T;.
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.33
N
LIST_S2
Benign
0.46
T;T
MetaRNN
Benign
0.0034
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-2.1
N;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
2.2
N;N
REVEL
Benign
0.28
Sift
Benign
0.97
T;T
Sift4G
Benign
0.82
T;T
Polyphen
0.0
B;.
Vest4
0.046
MPC
0.45
ClinPred
0.0080
T
GERP RS
5.9
Varity_R
0.097
gMVP
0.30

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: rs17683430; hg19: chr22-32487700; COSMIC: COSV56682960; API