rs121918239

chr9-137233404-G-Achr9-137233404-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_001177316.2(SLC34A3):c.756G>A(p.Gln252=) 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:4 B:3
• Conservation: PhyloP100: 3.96

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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 submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=2}. Variant chr9-137233404-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC34A3	NM_001177316.2	c.756G>A	p.Gln252=	splice_region_variant, synonymous_variant	7/13	ENST00000673835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC34A3	ENST00000673835.1	c.756G>A	p.Gln252=	splice_region_variant, synonymous_variant	7/13		NM_001177316.2	P1
SLC34A3	ENST00000361134.2	c.756G>A	p.Gln252=	splice_region_variant, synonymous_variant	7/13	2		P1
SLC34A3	ENST00000538474.5	c.756G>A	p.Gln252=	splice_region_variant, synonymous_variant	7/13	5		P1
SLC34A3	ENST00000673865.1	c.756G>A	p.Gln252=	splice_region_variant, synonymous_variant	7/10

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

GnomAD3 exomes AF: 0.00240 AC: 519 AN: 216202 Hom.: 2 AF XY: 0.00271 AC XY: 324 AN XY: 119682

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 SAS exome AF: 0.00730

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

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.000646

Gnomad4 ASJ exome AF: 0.0000771

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.00778

Gnomad4 FIN exome AF: 0.000394

Gnomad4 NFE exome AF: 0.00239

Gnomad4 OTH exome AF: 0.00145

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

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00196 Hom.: 1

Bravo AF: 0.00125

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive hypophosphatemic bone disease Pathogenic:1 Uncertain:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2006	- -
Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 16, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2022	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. -

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2022	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: 16358214, 34426522, 31589614, 31672324, 33716164, 33226606, 16849419) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 27, 2024

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121918239; hg19: chr9-140127856;