rs121918236

Positions:

chr9-137233722-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001177316.2(SLC34A3):c.846G>A(p.Pro282=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,612,238 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

SLC34A3
NM_001177316.2 splice_region, synonymous

Scores

Splicing: ADA: 0.9913

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 0.476

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-137233722-G-A is Pathogenic according to our data. Variant chr9-137233722-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1429.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC34A3	NM_001177316.2 linkuse as main transcript	c.846G>A	p.Pro282=	splice_region_variant, synonymous_variant	8/13	ENST00000673835.1	NP_001170787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SLC34A3	ENST00000673835.1 linkuse as main transcript	c.846G>A	p.Pro282=	splice_region_variant, synonymous_variant	8/13		NM_001177316.2	ENSP00000501114	P1
SLC34A3	ENST00000361134.2 linkuse as main transcript	c.846G>A	p.Pro282=	splice_region_variant, synonymous_variant	8/13	2		ENSP00000355353	P1
SLC34A3	ENST00000538474.5 linkuse as main transcript	c.846G>A	p.Pro282=	splice_region_variant, synonymous_variant	8/13	5		ENSP00000442397	P1
SLC34A3	ENST00000673865.1 linkuse as main transcript	c.846G>A	p.Pro282=	splice_region_variant, synonymous_variant	8/10			ENSP00000501101

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152028

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

249112

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135510

show subpopulations

Gnomad AFR exome

AF:

0.0000624

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000418

AC:

AN:

1460092

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726340

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive hypophosphatemic bone disease

Pathogenic:4Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 30, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2006	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 21, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing;in vitro	Laboratory of Functional Genomics, Research Centre for Medical Genetics	Aug 11, 2021	Synonymous variant c.846G>A in SLC34A3 could be classified as likely pathogenic variant according to ACMG criteria (PM2, PS3, PM3). The variant vas observed in 12 y.o. female patient with hypophosphatemic rickets with hypercalciuria in compound heterozygous state with c.1304delG variant in SLC34A3 gene. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change affects codon 282 of the SLC34A3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SLC34A3 protein. This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121918236, gnomAD 0.005%). This variant has been observed in individual(s) with hypophosphatemic rickets with hypercalciuria (PMID: 16358215, 31672324, 33223529, 34805638). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1429). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.72

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over