NM_144585.4:c.1145A>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP2PP3_ModeratePP5_Very_Strong

The NM_144585.4(SLC22A12):c.1145A>T(p.Gln382Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,611,934 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SLC22A12
NM_144585.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.73

Publications

15 publications found

Variant links:

Genes affected

SLC22A12 (HGNC:17989): (solute carrier family 22 member 12) The protein encoded by this gene is a member of the organic anion transporter (OAT) family, and it acts as a urate transporter to regulate urate levels in blood. This protein is an integral membrane protein primarily found in epithelial cells of the proximal tubule of the kidney. An elevated level of serum urate, hyperuricemia, is associated with increased incidences of gout, and mutations in this gene cause renal hypouricemia type 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

SLC22A12 Gene-Disease associations (from GenCC):

hypouricemia, renal 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hereditary renal hypouricemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC22A12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.37234 (below the threshold of 3.09). Trascript score misZ: 0.61926 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary renal hypouricemia, hypouricemia, renal 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

PP5

Variant 11-64599750-A-T is Pathogenic according to our data. Variant chr11-64599750-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 305239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A12	NM_144585.4 link	c.1145A>T	p.Gln382Leu	missense_variant	Exon 7 of 10	ENST00000377574.6	NP_653186.2	Q96S37-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A12	ENST00000377574.6 link	c.1145A>T	p.Gln382Leu	missense_variant	Exon 7 of 10	1	NM_144585.4	ENSP00000366797.1		Q96S37-1

Frequencies

GnomAD3 genomes

AF:

0.0000463

AC:

AN:

151122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00137

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000116

AC:

AN:

250488

AF XY:

0.000110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00158

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1460812

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00106

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111856

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000463

AC:

AN:

151122

Hom.:

Cov.:

AF XY:

0.0000542

AC XY:

AN XY:

73734

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41054

American (AMR)

AF:

0.00

AC:

AN:

15180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00137

AC:

AN:

5110

South Asian (SAS)

AF:

0.00

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67808

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dalmatian hypouricemia

Pathogenic:5

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM3_Strong+PP4+PS3_Supporting -

Sep 29, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC22A12 c.1145A>T (p.Gln382Leu) missense variant has been reported in two studies in which it is found in a compound heterozygous state in two individuals with renal hypouricemia, and in a heterozygous state in three unaffected family members (Ichida et al. 2004; Wakida et al. 2005). The p.Gln382Leu variant was absent from 75 controls and is reported at a frequency of 0.00093 in the East Asian population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes demonstrated that the p.Gln382Leu variant significantly decreased urate transport compared to wild type SLC22A12 (Ichida et al. 2004; Wakida et al. 2005). Based on the evidence, the p.Gln382Leu variant is classified as likely pathogenic for renal hypouricemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Feb 26, 2020

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLC22A12-related disorder

Pathogenic:1

Jan 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC22A12 c.1145A>T variant is predicted to result in the amino acid substitution p.Gln382Leu. This variant was reported to be causative for renal hypouricemia (Ichida et al. 2004. PubMed ID: 14694169; Lam et al. 2008. PubMed ID: 18760270; Zhou et al. 2019. PubMed ID: 31131560). Functional studies showed that this variant impairs the transport efficiency (Ichida et al. 2004. PubMed ID: 14694169; Toyoda et al. 2021. PubMed ID: 33821957). This variant is reported in 0.15% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-64367222-A-T). This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 382 of the SLC22A12 protein (p.Gln382Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypouricemia (PMID: 14694169, 15634722, 30097038, 31131560, 31591475). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 305239). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SLC22A12 function (PMID: 14694169, 15634722). For these reasons, this variant has been classified as Pathogenic. -

Familial renal hypouricemia

Pathogenic:1

Dec 06, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PP4, PS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

.;D;.;.;.

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.69

.;T;T;T;T

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.6

.;M;.;.;.

PhyloP100

5.7

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-5.6

D;D;D;D;D

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

0.98

D;D;D;.;.

Vest4

0.87

MutPred

0.88

.;Loss of helix (P = 0.2022);.;.;.;

MVP

0.91

MPC

0.87

ClinPred

0.33

GERP RS

3.6

Varity_R

0.74

gMVP

0.86

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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NM_144585.4:c.1145A>T

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