chr4-991538-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_022042.4(SLC26A1):c.166G>A(p.Ala56Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00063 in 1,605,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00063 ( 0 hom. )

Consequence

SLC26A1
NM_022042.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.25

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 1
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
Scheie syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
Hurler syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
Hurler-Scheie syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

IDUA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.36991975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A1	NM_022042.4 link	c.166G>A	p.Ala56Thr	missense_variant	Exon 2 of 3	ENST00000398516.3	NP_071325.2	Q9H2B4-1
IDUA	NM_000203.5 link	c.299+3589C>T		intron_variant	Intron 2 of 13	ENST00000514224.2	NP_000194.2	P35475-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A1	ENST00000398516.3 link	c.166G>A	p.Ala56Thr	missense_variant	Exon 2 of 3	1	NM_022042.4	ENSP00000381528.2		Q9H2B4-1
IDUA	ENST00000514224.2 link	c.299+3589C>T		intron_variant	Intron 2 of 13	2	NM_000203.5	ENSP00000425081.2		P35475-1

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000560

AC:

134

AN:

239334

AF XY:

0.000520

show subpopulations

Gnomad AFR exome

AF:

0.000454

Gnomad AMR exome

AF:

0.000998

Gnomad ASJ exome

AF:

0.00117

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000511

Gnomad NFE exome

AF:

0.000682

Gnomad OTH exome

AF:

0.000510

GnomAD4 exome

AF:

0.000630

AC:

916

AN:

1453170

Hom.:

Cov.:

AF XY:

0.000602

AC XY:

435

AN XY:

722256

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33386

American (AMR)

AF:

0.000901

AC:

AN:

44396

Ashkenazi Jewish (ASJ)

AF:

0.00124

AC:

AN:

25776

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.000117

AC:

AN:

85750

European-Finnish (FIN)

AF:

0.000278

AC:

AN:

50360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.000696

AC:

771

AN:

1108088

Other (OTH)

AF:

0.000716

AC:

AN:

60096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

111

166

222

277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000624

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41578

American (AMR)

AF:

0.00131

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000764

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000497

Hom.:

Bravo

AF:

0.000695

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000489

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 56 of the SLC26A1 protein (p.Ala56Thr). This variant is present in population databases (rs142573758, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with nephrolithiasis (PMID: 27125215, 27210743). ClinVar contains an entry for this variant (Variation ID: 242376). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jul 20, 2016

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nephrolithiasis susceptibility caused by SLC26A1;C5830511:Hypersulfaturia

Uncertain:1

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

.;.;T;T

Eigen

Benign

0.019

Eigen_PC

Benign

-0.040

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.82

.;T;.;T

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.5

L;L;L;L

PhyloP100

3.3

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.39

N;.;N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.010

D;.;D;D

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

0.95

.;.;P;P

Vest4

0.71

MVP

0.90

MPC

0.30

ClinPred

0.055

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.095

gMVP

0.57

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over