rs139024319

Positions:

chr4-991150-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_022042.4(SLC26A1):c.554C>T(p.Thr185Met) variant causes a missense change. The variant allele was found at a frequency of 0.000294 in 1,552,418 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 0.00018 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

SLC26A1
NM_022042.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.76

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

PP5

Variant 4-991150-G-A is Pathogenic according to our data. Variant chr4-991150-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242374.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr4-991150-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.554C>T	p.Thr185Met	missense_variant	2/3	ENST00000398516.3	NP_071325.2
IDUA	NM_000203.5 linkuse as main transcript	c.299+3201G>A		intron_variant		ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A1	ENST00000398516.3 linkuse as main transcript	c.554C>T	p.Thr185Met	missense_variant	2/3	1	NM_022042.4	ENSP00000381528	P1	Q9H2B4-1
IDUA	ENST00000514224.2 linkuse as main transcript	c.299+3201G>A		intron_variant		2	NM_000203.5	ENSP00000425081	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000254

AC:

AN:

204950

Hom.:

AF XY:

0.000211

AC XY:

AN XY:

109000

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000331

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000505

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000316

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000306

AC:

429

AN:

1400092

Hom.:

Cov.:

AF XY:

0.000313

AC XY:

215

AN XY:

687962

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000274

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000128

Gnomad4 SAS exome

AF:

0.0000131

Gnomad4 FIN exome

AF:

0.0000605

Gnomad4 NFE exome

AF:

0.000359

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000184

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000399

Hom.:

Bravo

AF:

0.000196

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000216

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Likely 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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 185 of the SLC26A1 protein (p.Thr185Met). This variant is present in population databases (rs139024319, gnomAD 0.04%). This missense change has been observed in individual(s) with nephrolithiasis (PMID: 27210743, 30586318). ClinVar contains an entry for this variant (Variation ID: 242374). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A1 protein function. 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. -

Calcium oxalate urolithiasis

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.554C>T variant is predicted to result in the amino acid substitution p.Thr185Met. This variant has been reported in the compound heterozygous state with the p.Ser358Leu variant in an individual with nephrolithiasis (Gee et al. 2016. PubMed ID: 27210743). In a separate study, this variant was reported in a patient with nephropathy; however, this patient also had the p.Ser358Leu variant (phase was not determined) and a variant in INF2 (Patient CDK250 in Table S7, Groopman. 2019 et al. PubMed ID: 30586318). In addition, the p.Thr185Met and p.Ser358Leu variants were documented separately in individuals from the German Chronic Kidney Disease (GCKD) cohort (Pfau et al. 2023. PubMed ID: 36719378). Functional studies have shown that the p.Thr185Met variant causes a defect in protein folding/trafficking and an ~25% reduction of transport activity, supportive of dominant negative effect (Groopman et al. 2018. PubMed ID: 30586318; Pfau et al. 2023. PubMed ID 36719378). This variant is reported in 0.046% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations in ClinVar ranging from pathogenic to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/242374/). It has been noted that 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). 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

Benign

0.34

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

.;.;D;D

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

.;D;.;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.4

D;.;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;.;D;D

Vest4

0.87

MVP

0.98

MPC

0.56

ClinPred

0.65

GERP RS

5.4

Varity_R

0.82

gMVP

0.93

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