rs121907896

Variant names:

• chr11-64591825-G-A
• rs121907896
• NM_144585.4:c.269G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PS3 PP2 PP5_Very_Strong BP4

The NM_144585.4(SLC22A12):​c.269G>A​(p.Arg90His) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,612,014 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000372972: Ichida et al. (2004) demonstrated that urate transport activity for the p.Arg90His variant in Xenopus oocytes was significantly decreased in comparison with that of wild type and was similar to that of oocytes that were not injected with URAT1 cRNA. Ichida et al. (2004) also demonstrated through immunocytochemical analysis that the variant exhibited similar staining patterns to wild type in the plasma membrane of Xenopus oocytes." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: SLC22A12 NM_144585.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.17
• Publications: 56 publications found

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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hereditary renal hypouricemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000372972: Ichida et al. (2004) demonstrated that urate transport activity for the p.Arg90His variant in Xenopus oocytes was significantly decreased in comparison with that of wild type and was similar to that of oocytes that were not injected with URAT1 cRNA. Ichida et al. (2004) also demonstrated through immunocytochemical analysis that the variant exhibited similar staining patterns to wild type in the plasma membrane of Xenopus oocytes.; SCV000967684: "In vitro functional studies support an impact to protein function (Ichida 2004)."; SCV003439814: Experimental studies have shown that this missense change affects SLC22A12 function (PMID: 33821957).
• 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.
• PP5: Variant 11-64591825-G-A is Pathogenic according to our data. Variant chr11-64591825-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1300683). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144585.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A12	NM_144585.4	MANE Select	c.269G>A	p.Arg90His	missense	Exon 1 of 10	NP_653186.2
	SLC22A12	NM_001276326.2		c.269G>A	p.Arg90His	missense	Exon 1 of 10	NP_001263255.1	Q96S37-4
	SLC22A12	NM_001276327.2		c.269G>A	p.Arg90His	missense	Exon 1 of 8	NP_001263256.1	Q96S37-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A12	ENST00000377574.6	TSL:1 MANE Select	c.269G>A	p.Arg90His	missense	Exon 1 of 10	ENSP00000366797.1	Q96S37-1
	SLC22A12	ENST00000336464.7	TSL:1	c.269G>A	p.Arg90His	missense	Exon 1 of 10	ENSP00000336836.7	Q96S37-4
	SLC22A12	ENST00000377572.5	TSL:1	c.269G>A	p.Arg90His	missense	Exon 1 of 8	ENSP00000366795.1	Q96S37-2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000178 AC: 44 AN: 246684 AF XY: 0.000224

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00211

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1459718 Hom.: 1 Cov.: 35 AF XY: 0.000107 AC XY: 78 AN XY: 726262

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00292 AC: 116 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111964

Other (OTH) AF: 0.0000331 AC: 2 AN: 60374

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74468

African (AFR) AF: 0.000144 AC: 6 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Dalmatian hypouricemia (6)
1	-	-	Familial renal hypouricemia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.2
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.32
Sift	Benign	0.061	T
Sift4G	Uncertain	0.029	D
Polyphen		0.97	D
Vest4		0.25
MPC		0.96
ClinPred		0.29	T
GERP RS		3.5
Varity_R		0.30
gMVP		0.72
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121907896; hg19: chr11-64359297;