rs121918239

Variant names:

• chr9-137233404-G-A
• rs121918239
• NM_001177316.2:c.756G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-137233404-G-A
• chr9-137233404-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_001177316.2(SLC34A3):​c.756G>A​(p.Gln252Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00232 in 1,600,354 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (14 hom.)
• Consequence: SLC34A3 NM_001177316.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.9948
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:3
• Conservation: PhyloP100: 3.96
• Publications: 8 publications found

Genes affected

SLC34A3 (HGNC:20305): (solute carrier family 34 member 3) This gene encodes a member of SLC34A transporter family of proteins, and is expressed primarily in the kidney. It is involved in transporting phosphate into cells via sodium cotransport in the renal brush border membrane, and contributes to the maintenance of inorganic phosphate concentration in the kidney. Mutations in this gene are associated with hereditary hypophosphatemic rickets with hypercalciuria. Alternatively spliced transcript variants varying in the 5' UTR have been found for this gene.[provided by RefSeq, Apr 2010]

SLC34A3 Gene-Disease associations (from GenCC):

• hereditary hypophosphatemic rickets with hypercalciuria

  Inheritance: SD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 9-137233404-G-A is Benign according to our data. Variant chr9-137233404-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1434.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00163 (248/152236) while in subpopulation SAS AF = 0.00622 (30/4820). AF 95% confidence interval is 0.00448. There are 0 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 SD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC34A3	NM_001177316.2	c.756G>A	p.Gln252Gln	splice_region_variant, synonymous_variant	Exon 7 of 13	ENST00000673835.1	NP_001170787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC34A3	ENST00000673835.1	c.756G>A	p.Gln252Gln	splice_region_variant, synonymous_variant	Exon 7 of 13		NM_001177316.2	ENSP00000501114.1
SLC34A3	ENST00000361134.2	c.756G>A	p.Gln252Gln	splice_region_variant, synonymous_variant	Exon 7 of 13	2		ENSP00000355353.2
SLC34A3	ENST00000538474.5	c.756G>A	p.Gln252Gln	splice_region_variant, synonymous_variant	Exon 7 of 13	5		ENSP00000442397.1
SLC34A3	ENST00000673865.1	c.756G>A	p.Gln252Gln	splice_region_variant, synonymous_variant	Exon 7 of 10			ENSP00000501101.1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00240 AC: 519 AN: 216202 AF XY: 0.00271

Gnomad AFR exome AF: 0.000649

Gnomad AMR exome AF: 0.000587

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.0000611

Gnomad FIN exome AF: 0.000239

Gnomad NFE exome AF: 0.00277

Gnomad OTH exome AF: 0.00239

GnomAD4 exome AF: 0.00239 AC: 3465 AN: 1448118 Hom.: 14 Cov.: 36 AF XY: 0.00254 AC XY: 1826 AN XY: 719966

African (AFR) AF: 0.000181 AC: 6 AN: 33222

American (AMR) AF: 0.000646 AC: 28 AN: 43368

Ashkenazi Jewish (ASJ) AF: 0.0000771 AC: 2 AN: 25942

East Asian (EAS) AF: 0.0000511 AC: 2 AN: 39110

South Asian (SAS) AF: 0.00778 AC: 662 AN: 85122

European-Finnish (FIN) AF: 0.000394 AC: 19 AN: 48176

Middle Eastern (MID) AF: 0.00231 AC: 13 AN: 5638

European-Non Finnish (NFE) AF: 0.00239 AC: 2646 AN: 1107730

Other (OTH) AF: 0.00145 AC: 87 AN: 59810

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74436

African (AFR) AF: 0.000602 AC: 25 AN: 41554

American (AMR) AF: 0.000914 AC: 14 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00259 AC: 176 AN: 67986

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00198 Hom.: 2

Bravo AF: 0.00125

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive hypophosphatemic bone disease Pathogenic:1 Uncertain:5

May 01, 2025

Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

ACMG: PS1, PP3 -

Apr 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypophosphatemic rickets with hypercalciuria (MIM#241530). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Approximately 45% of compound heterozygotes present with rickets (PMID: 32524022). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). The substitution affects the last nucleotide of exon 7. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 558 heterozygotes, 2 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable non-canonical splice site variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported in a single compound heterozygous proband with hypophosphatemic rickets with hypercalciuria (MIM#241530). However, only this gene was sequenced and RNA studies were not done to conclusively prove that this otherwise synonymous variant, leads to aberrant splicing (PMID: 16849419). This variant has also been reported in a kidney disease patient for whom another causative variant was identified (PMID: 33226606). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 31, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC34A3 c.756G>A; p.Gln252= variant (rs121918239) is described in the literature in 3 affected individuals who also carried an additional SLC34A3 variant (Hureaux 2019, Ichikawa 2006, Vaisitti 2021). The variant is listed in the ClinVar database (Variation ID: 1434) and is reported in the South Asian population with an allele frequency of 0.7% (211/28,892 alleles including 2 homozygotes) in the Genome Aggregation Database. This is a synonymous variant in the last nucleotide of exon 7, a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of functional data and the relatively high population frequency, the significance of the p.Gln252= variant is uncertain at this time. References: Hureaux M et al. High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults. Kidney Int. 2019 Dec;96(6):1408-1416. PMID: 31672324. Ichikawa S et al. Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab. 2006 Oct;91(10):4022-7. PMID: 16849419. Vaisitti T et al. Clinical exome sequencing is a powerful tool in the diagnostic flow of monogenic kidney diseases: an Italian experience. J Nephrol. 2021 Oct;34(5):1767-1781. PMID: 33226606. -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

NM_080877.2:c.756G>A in the SLC34A3 gene has an allele frequency of 0.007 in South Asian subpopulation in the gnomAD database. It is a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site and the nucleotide is not highly conserved. One affected individual with hereditary hypophosphatemic rickets with hypercalciuria was a compound heterozygote for this variant and an 85-bp deletion in intron 10 (PMID: 16849419). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BP7, PM3, PP4. -

not provided Uncertain:1 Benign:2

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SLC34A3: PP3, BS2 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing; This variant is associated with the following publications: (PMID: 34805638, 16358214, 34426522, 31589614, 31672324, 33716164, 33226606, 33852231, 36699160, 35689455, 16849419) -

SLC34A3-related disorder Uncertain:1

Mar 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC34A3 c.756G>A variant is not predicted to result in an amino acid change (p.=). This variant occurs at the last base of exon 7 and is predicted to alter splicing by splicing prediction programs. It has been reported in patients affected by hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and suspected to affect normal splicing, but no experimental evidence was presented to support a splice effect (Ichikawa et al. 2006. PubMed ID: 16849419, reported as g.1702G>A; Bergwitz et al. 2006. PubMed ID: 16358214; Hureaux et al 2019. PubMed ID: 31672324). In the Ichikawa et al. study, the c.756G>A (p.Gln252Gln) variant was found in a compound heterozygous state with a suspected pathogenic 85bp deletion in intron 10 in a patient with HHRH. This variant is reported in 0.73% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be a benign, we classify c.756G>A (p.Gln252Gln) as a variant of uncertain significance due to insufficient and conflicting evidence. -

not specified Benign:1

Feb 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC34A3 c.756G>A (p.Gln252Gln) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. One predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0024 in 216202 control chromosomes, predominantly at a frequency of 0.0073 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC34A3 causing Hereditary Hypophosphatemic Rickets With Hypercalciuria phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.756G>A has been reported in the literature in individuals affected with Hereditary Hypophosphatemic Rickets With Hypercalciuria and renal hypophosphatemia (example, Hureaux_2019, Ichikawa_2006, Karakilic-Ozturan_2023, Sturznickel_2022), without strong evidence for causality. These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (SLC34A3 c.586G>A, p.Gly196Arg at a homozygous state with the homozygous variant of interest in a patient with HHRH), providing supporting evidence for a benign role (Sturznickel_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31672324, 16849419, 36699160, 35689455). ClinVar contains an entry for this variant (Variation ID: 1434). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Benign	0.97
PhyloP100		4.0
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.65		Position offset: -36

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121918239; hg19: chr9-140127856; COSMIC: COSV107457502; COSMIC: COSV107457502;