chr22-32043378-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000343.4(SLC5A1):​c.97G>A​(p.Val33Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,614,118 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 2 hom. )

Consequence

SLC5A1
NM_000343.4 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.36
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 -12 ACMG points.

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=0.012450963).
BP6
Variant 22-32043378-G-A is Benign according to our data. Variant chr22-32043378-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 903163.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000158 (24/152316) while in subpopulation EAS AF= 0.00444 (23/5186). AF 95% confidence interval is 0.00303. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC5A1NM_000343.4 linkuse as main transcriptc.97G>A p.Val33Ile missense_variant 1/15 ENST00000266088.9 NP_000334.1
SLC5A1XM_011530331.2 linkuse as main transcriptc.97G>A p.Val33Ile 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.97G>A p.Val33Ile missense_variant 1/151 NM_000343.4 ENSP00000266088 P1P13866-1

Frequencies

GnomAD3 genomes
AF:
0.000158
AC:
24
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00442
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000219
AC:
55
AN:
250696
Hom.:
1
AF XY:
0.000207
AC XY:
28
AN XY:
135562
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00288
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000171
AC:
250
AN:
1461802
Hom.:
2
Cov.:
31
AF XY:
0.000187
AC XY:
136
AN XY:
727188
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00600
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152316
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74486
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00444
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000618
Hom.:
0
Bravo
AF:
0.000147
ExAC
AF:
0.000247
AC:
30
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Congenital glucose-galactose malabsorption Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 03, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
15
DANN
Uncertain
1.0
DEOGEN2
Benign
0.095
T
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.012
T
MetaSVM
Uncertain
-0.28
T
MutationAssessor
Uncertain
2.2
M
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.73
N
REVEL
Benign
0.23
Sift
Benign
0.11
T
Sift4G
Benign
0.14
T
Polyphen
0.12
B
Vest4
0.27
MVP
0.85
MPC
0.38
ClinPred
0.052
T
GERP RS
2.8
Varity_R
0.067
gMVP
0.49

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: rs33918436; hg19: chr22-32439365; COSMIC: COSV105065838; COSMIC: COSV105065838; API