22-32043331-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000343.4(SLC5A1):c.50T>C(p.Val17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,198 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (17 hom.)
• Consequence: SLC5A1 NM_000343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.288

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLC5A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0038532317).
• BP6: Variant 22-32043331-T-C is Benign according to our data. Variant chr22-32043331-T-C is described in ClinVar as [Benign]. Clinvar id is 789620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00729 (1111/152338) while in subpopulation AFR AF= 0.024 (999/41578). AF 95% confidence interval is 0.0228. There are 15 homozygotes in gnomad4. There are 477 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A1	NM_000343.4	c.50T>C	p.Val17Ala	missense_variant	1/15	ENST00000266088.9
SLC5A1	XM_011530331.2	c.50T>C	p.Val17Ala	missense_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A1	ENST00000266088.9	c.50T>C	p.Val17Ala	missense_variant	1/15	1	NM_000343.4	P1

Frequencies

GnomAD3 genomes AF: 0.00728 AC: 1108 AN: 152220 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00242 AC: 606 AN: 250766 Hom.: 4 AF XY: 0.00183 AC XY: 248 AN XY: 135634

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00108 AC: 1579 AN: 1461860 Hom.: 17 Cov.: 32 AF XY: 0.000994 AC XY: 723 AN XY: 727228

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00729 AC: 1111 AN: 152338 Hom.: 15 Cov.: 32 AF XY: 0.00640 AC XY: 477 AN XY: 74496

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00189 Hom.: 8

Bravo AF: 0.00821

ESP6500AA AF: 0.0254 AC: 112

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00263 AC: 319

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital glucose-galactose malabsorption Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	5.0
Dann	Benign	0.30
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.050	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.18
Sift	Benign	0.55	T
Sift4G	Benign	0.86	T
Polyphen		0.0020	B
Vest4		0.10
MVP		0.66
MPC		0.56
ClinPred		0.0090	T
GERP RS		2.5
Varity_R		0.046
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

Other links and lift over

dbSNP: rs33951240; hg19: chr22-32439318; COSMIC: COSV105065852; COSMIC: COSV105065852;