rs73219719

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_022042.4(SLC26A1):c.1115G>T(p.Arg372Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000437 in 1,580,256 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R372H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

SLC26A1
NM_022042.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0440

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A1	NM_022042.4 linkuse as main transcript	c.1115G>T	p.Arg372Leu	missense_variant	3/3	ENST00000398516.3
IDUA	NM_000203.5 linkuse as main transcript	c.299+1875C>A		intron_variant		ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A1	ENST00000398516.3 linkuse as main transcript	c.1115G>T	p.Arg372Leu	missense_variant	3/3	1	NM_022042.4	P1	Q9H2B4-1
IDUA	ENST00000514224.2 linkuse as main transcript	c.299+1875C>A		intron_variant		2	NM_000203.5	P1	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000363

AC:

AN:

192628

Hom.:

AF XY:

0.0000478

AC XY:

AN XY:

104506

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000728

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000462

AC:

AN:

1428006

Hom.:

Cov.:

AF XY:

0.0000438

AC XY:

AN XY:

707208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000252

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000575

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000818

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000168

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperoxaluria

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Institute of Human Genetics, University of Leipzig Medical Center

May 15, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 29, 2023

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 372 of the SLC26A1 protein (p.Arg372Leu). This variant is present in population databases (rs73219719, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SLC26A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2502382). 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 not expected to disrupt SLC26A1 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.15

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;D

Eigen

Benign

-0.062

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.26

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Uncertain

0.24

MutationAssessor

Uncertain

2.0

M;M

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.41

Sift

Benign

0.050

D;D

Sift4G

Uncertain

0.025

D;D

Polyphen

0.90

P;P

Vest4

0.55

MVP

0.91

MPC

0.49

ClinPred

0.30

GERP RS

3.4

Varity_R

0.23

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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