rs148832260

Positions:

chr4-989866-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_022042.4(SLC26A1):c.1073C>T(p.Ser358Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,576,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

SLC26A1
NM_022042.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 7.95

Variant links:

Genes affected

SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]

SLC26A1 links:

IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]

IDUA links:

SLC26A1 (HGNC:):

SLC26A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

PP5

Variant 4-989866-G-A is Pathogenic according to our data. Variant chr4-989866-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242375.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chr4-989866-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A1	NM_022042.4 linkuse as main transcript	c.1073C>T	p.Ser358Leu	missense_variant	3/3	ENST00000398516.3	NP_071325.2	Q9H2B4-1
IDUA	NM_000203.5 linkuse as main transcript	c.299+1917G>A		intron_variant		ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A1	ENST00000398516.3 linkuse as main transcript	c.1073C>T	p.Ser358Leu	missense_variant	3/3	1	NM_022042.4	ENSP00000381528.2		Q9H2B4-1
IDUA	ENST00000514224.2 linkuse as main transcript	c.299+1917G>A		intron_variant		2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.000328

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000280

AC:

AN:

185846

Hom.:

AF XY:

0.000239

AC XY:

AN XY:

100450

show subpopulations

Gnomad AFR exome

AF:

0.0000949

Gnomad AMR exome

AF:

0.000107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000708

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000575

Gnomad OTH exome

AF:

0.000405

GnomAD4 exome

AF:

0.000389

AC:

554

AN:

1423850

Hom.:

Cov.:

AF XY:

0.000399

AC XY:

281

AN XY:

704628

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.000103

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000264

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000409

Gnomad4 NFE exome

AF:

0.000486

Gnomad4 OTH exome

AF:

0.000237

GnomAD4 genome

AF:

0.000328

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74528

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000487

Hom.:

Bravo

AF:

0.000283

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000471

AC:

ExAC

AF:

0.000144

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 358 of the SLC26A1 protein (p.Ser358Leu). This variant is present in population databases (rs148832260, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with nephrolithiasis (PMID: 27210743, 30586318). ClinVar contains an entry for this variant (Variation ID: 242375). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC26A1 function (PMID: 27210743, 36719378). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2020	- -

Nephrolithiasis, calcium oxalate

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 2023	- -

SLC26A1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

The SLC26A1 c.1073C>T variant is predicted to result in the amino acid substitution p.Ser358Leu. This variant has been reported in the compound heterozygous state with the p.Thr185Met variant in a single individual with nephrolithiasis (Table 1, Gee et al. 2016. PubMed ID: 27210743). In vitro experimental studies suggest this variant impairs sulfate-bicarbonate exchange activity and sulfate uptake (Figure 4, Gee et al. 2016. PubMed ID: 27210743; Figure 8, Pfau et al. 2023. PubMed ID: 36719378). An additional study reported this variant as occurring in heterozygous carriers from the German Chronic Kidney Disease (GCKD) cohort, but rare SLC26A1 heterozygous carriers did not have a higher prevalence of self-reported kidney stones (Pfau et al. 2023. PubMed ID: 36719378). In addition, this study indicates further evidence is needed to clarify the association of biallelic variants in SLC26A1 with disease per ClinGen criteria (Pfau et al. 2023. PubMed ID: 36719378). This variant is reported in 0.055% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

D;D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.5

H;H

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.87

MVP

0.99

MPC

0.52

ClinPred

0.75

GERP RS

5.2

Varity_R

0.86

gMVP

0.96

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over