22-32043316-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000343.4(SLC5A1):c.35C>T(p.Ala12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,614,188 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A12T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (7 hom.)
• Consequence: SLC5A1 NM_000343.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.11

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC5A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.004654914).
• BP6: Variant 22-32043316-C-T is Benign according to our data. Variant chr22-32043316-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 502121.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000919 (140/152354) while in subpopulation AMR AF= 0.00118 (18/15308). AF 95% confidence interval is 0.00076. There are 0 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A1	NM_000343.4	c.35C>T	p.Ala12Val	missense_variant	1/15	ENST00000266088.9
SLC5A1	XM_011530331.2	c.35C>T	p.Ala12Val	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A1	ENST00000266088.9	c.35C>T	p.Ala12Val	missense_variant	1/15	1	NM_000343.4	P1

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00113 AC: 284 AN: 250746 Hom.: 5 AF XY: 0.00128 AC XY: 174 AN XY: 135618

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000608

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000631 AC: 922 AN: 1461834 Hom.: 7 Cov.: 32 AF XY: 0.000674 AC XY: 490 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0145

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000997

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000307

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74500

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00123 Hom.: 2

Bravo AF: 0.000854

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000955 AC: 116

EpiCase AF: 0.00125

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital glucose-galactose malabsorption Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

SLC5A1: PM2:Supporting, PP4, BP4 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	10
Dann	Uncertain	0.99
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.51
Sift	Benign	0.061	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.061
MVP		0.75
MPC		0.46
ClinPred		0.017	T
GERP RS		3.7
Varity_R		0.067
gMVP		0.27

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

Other links and lift over

dbSNP: rs150288967; hg19: chr22-32439303;