9-137232928-G-A

Position:

chr9-137232928-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001177316.2(SLC34A3):c.448+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,606,892 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

SLC34A3
NM_001177316.2 splice_donor, intron

Scores

Splicing: ADA: 0.9998

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 3.24

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.079444446 fraction of the gene. Cryptic splice site detected, with MaxEntScore 1.8, offset of -22, new splice context is: gtgGTcagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-137232928-G-A is Pathogenic according to our data. Variant chr9-137232928-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 445687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC34A3	NM_001177316.2 linkuse as main transcript	c.448+1G>A		splice_donor_variant, intron_variant		ENST00000673835.1	NP_001170787.2	Q8N130

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC34A3	ENST00000673835.1 linkuse as main transcript	c.448+1G>A		splice_donor_variant, intron_variant			NM_001177316.2	ENSP00000501114.1		Q8N130

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000157

AC:

AN:

235288

Hom.:

AF XY:

0.000180

AC XY:

AN XY:

127954

show subpopulations

Gnomad AFR exome

AF:

0.0000684

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000682

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000314

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.000398

AC:

579

AN:

1454790

Hom.:

Cov.:

AF XY:

0.000366

AC XY:

265

AN XY:

723334

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.0000578

Gnomad4 NFE exome

AF:

0.000474

Gnomad4 OTH exome

AF:

0.000765

GnomAD4 genome

AF:

0.000158

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000344

Hom.:

Bravo

AF:

0.000208

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000166

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change affects a donor splice site in intron 5 of the SLC34A3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC34A3 are known to be pathogenic (PMID: 16358214, 16358215, 22159077). This variant is present in population databases (rs150841256, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. Disruption of this splice site has been observed in individual(s) with hypophosphatemic rickets with hypercalciuria (PMID: 21344632, 31440709). ClinVar contains an entry for this variant (Variation ID: 445687). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SLC34A3: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2017	The c.448+1G>A variant in the SLC34A3 gene has been reported previously, using alternate nomenclature g.1226G>A, in an individual with HHRH who was compound heterozygous for c.448+1G>A and another SLC34A3 variant (Phulwani et al., 2011). RT-PCR studies of c.448+1G>A indicate that it creates an alternative splice donor site upstream of the natural splice donor site in intron 5, leading to a frameshift and a truncated transcript (Phulwani et al., 2011). The c.448+1G>A variant is observed in 35/118640 (0.03%) alleles from individuals of non-Finnish European background and in 39/261838 (0.015%) total alleles, including one homozygous individual, in large population cohorts (Lek et al., 2016). We interpret c.448+1G>A as a likely pathogenic variant. -

Autosomal recessive hypophosphatemic bone disease

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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) 0108 - This gene is associated with both recessive and dominant disease. Monoallelic inheritance has been reported in association with mild hypercalciuria, mild hypophosphatemia, and an absence of rickets or bone disease (OMIM; PMIDs: 16358214, 22806288, 21344632). (I) 0115 - Variants in this gene are known to have variable expressivity. Approximately 45% of compound heterozygotes present with rickets (PMID: 32524022). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). RT-PCR on lymphoblastoid cells of an affected compound heterozygous individual suggests this variant results in deletion of the the first 22 nucleotides in exon 5, predicted to cause a frameshift and truncated protein. However, data was not shown (PMID: 21344632). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 39 heterozygotes, 1 homozygote). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The c.448+5G>A variant has been reported in three related individuals, a homozygous father with hereditary hypophosphatemic rickets with hypercalciuria and two male heterozygous offspring presenting with mild hypercalciuria (PMID: 22806288). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in compound heterozygous and heterozygous individuals with hereditary hypophosphatemic rickets with hypercalciuria (PMIDs: 21344632, 34805638; 31440709). It has also been reported as pathogenic/likely pathogenic by multiple clinical laboratories (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Benign

0.96

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.84

GERP RS

3.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: 3

DS_DL_spliceai

0.91

Position offset: -1

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