rs33954001

Positions:

• chr22-32110063-C-G
• chr22-32110063-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000343.4(SLC5A1):​c.1845C>G​(p.His615Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0655 in 1,613,006 control chromosomes in the GnomAD database, including 3,936 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 (★★). Synonymous variant affecting the same amino acid position (i.e. H615H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (206 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3730 hom.)
• Consequence: SLC5A1 NM_000343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.134

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]

LOC105373000 (HGNC:):

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=0.0018596649).
• BP6: Variant 22-32110063-C-G is Benign according to our data. Variant chr22-32110063-C-G is described in ClinVar as [Benign]. Clinvar id is 341263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A1	NM_000343.4	c.1845C>G	p.His615Gln	missense_variant	15/15	ENST00000266088.9
LOC105373000	XR_938172.3	n.408-3121G>C		intron_variant, non_coding_transcript_variant
SLC5A1	NM_001256314.2	c.1464C>G	p.His488Gln	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A1	ENST00000266088.9	c.1845C>G	p.His615Gln	missense_variant	15/15	1	NM_000343.4	P1
SLC5A1	ENST00000543737.2	c.1464C>G	p.His488Gln	missense_variant	14/14	2

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6850 AN: 152090 Hom.: 207 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0374

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0706

Gnomad OTH AF: 0.0369

GnomAD3 exomes AF: 0.0485 AC: 12189 AN: 251408 Hom.: 373 AF XY: 0.0495 AC XY: 6724 AN XY: 135868

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0382

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.0390

Gnomad FIN exome AF: 0.0516

Gnomad NFE exome AF: 0.0703

Gnomad OTH exome AF: 0.0451

GnomAD4 exome AF: 0.0676 AC: 98770 AN: 1460798 Hom.: 3730 Cov.: 31 AF XY: 0.0668 AC XY: 48572 AN XY: 726754

Gnomad4 AFR exome AF: 0.00986

Gnomad4 AMR exome AF: 0.0319

Gnomad4 ASJ exome AF: 0.0408

Gnomad4 EAS exome AF: 0.00184

Gnomad4 SAS exome AF: 0.0423

Gnomad4 FIN exome AF: 0.0565

Gnomad4 NFE exome AF: 0.0770

Gnomad4 OTH exome AF: 0.0579

GnomAD4 genome AF: 0.0450 AC: 6851 AN: 152208 Hom.: 206 Cov.: 32 AF XY: 0.0435 AC XY: 3234 AN XY: 74414

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0378

Gnomad4 FIN AF: 0.0557

Gnomad4 NFE AF: 0.0706

Gnomad4 OTH AF: 0.0365

Alfa AF: 0.0538 Hom.: 154

Bravo AF: 0.0428

TwinsUK AF: 0.0747 AC: 277

ALSPAC AF: 0.0810 AC: 312

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0699 AC: 601

ExAC AF: 0.0500 AC: 6073

EpiCase AF: 0.0603

EpiControl AF: 0.0659

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital glucose-galactose malabsorption Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.8
DANN	Benign	0.28
DEOGEN2	Benign	0.041	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.010	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.21
Sift	Benign	0.65	T;T
Sift4G	Benign	0.79	T;T
Polyphen		0.0	B;.
Vest4		0.012
MutPred		0.41		Gain of loop (P = 0.1081);.;
MPC		0.47
ClinPred		0.0016	T
GERP RS		2.9
Varity_R		0.040
gMVP		0.14

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: rs33954001; hg19: chr22-32506050;