rs142573758

chr4-991538-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36991975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A1	NM_022042.4	c.166G>A	p.Ala56Thr	missense_variant	2/3	ENST00000398516.3
IDUA	NM_000203.5	c.299+3589C>T		intron_variant		ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A1	ENST00000398516.3	c.166G>A	p.Ala56Thr	missense_variant	2/3	1	NM_022042.4	P1
IDUA	ENST00000514224.2	c.299+3589C>T		intron_variant		2	NM_000203.5	P1

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

GnomAD3 exomes AF: 0.000560 AC: 134 AN: 239334 Hom.: 0 AF XY: 0.000520 AC XY: 68 AN XY: 130716

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 SAS exome AF: 0.000167

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

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000901

Gnomad4 ASJ exome AF: 0.00124

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.000278

Gnomad4 NFE exome AF: 0.000696

Gnomad4 OTH exome AF: 0.000716

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

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.00142

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

Uncertain significance, no assertion criteria provided	literature only	OMIM	Jul 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 16, 2023	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). 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. -

Nephrolithiasis, calcium oxalate Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 14, 2022

- -

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
Eigen	Benign	0.019
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.61	D
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
MutationTaster	Benign	1.0	D;D;N;N;N
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

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

Other links and lift over

dbSNP: rs142573758; hg19: chr4-985326;