NM_022042.4:c.166G>A

Variant names:

• chr4-991538-C-T
• rs142573758
• NM_022042.4:c.166G>A

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.25
• Publications: 2 publications found

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]

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

ACMG classification

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	c.166G>A	p.Ala56Thr	missense_variant	Exon 2 of 3	ENST00000398516.3	NP_071325.2
IDUA	NM_000203.5	c.299+3589C>T		intron_variant	Intron 2 of 13	ENST00000514224.2	NP_000194.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152216 Hom.: 0 Cov.: 34

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

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.: 0 Cov.: 32 AF XY: 0.000602 AC XY: 435 AN XY: 722256

African (AFR) AF: 0.000180 AC: 6 AN: 33386

American (AMR) AF: 0.000901 AC: 40 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 32 AN: 25776

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85750

European-Finnish (FIN) AF: 0.000278 AC: 14 AN: 50360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.000696 AC: 771 AN: 1108088

Other (OTH) AF: 0.000716 AC: 43 AN: 60096

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152334 Hom.: 0 Cov.: 34 AF XY: 0.000604 AC XY: 45 AN XY: 74498

African (AFR) AF: 0.000265 AC: 11 AN: 41578

American (AMR) AF: 0.00131 AC: 20 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000497 Hom.: 0

Bravo AF: 0.000695

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000489 AC: 59

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

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	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;.;T;T
Eigen	Benign	0.019
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.82	.;T;.;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.5	L;L;L;L
PhyloP100		3.3
PrimateAI	Benign	0.41	T
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	T
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

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

Other links and lift over

dbSNP: rs142573758; hg19: chr4-985326;