rs148976897

Positions:

• chr5-177386432-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003052.5(SLC34A1):​c.398C>T​(p.Ala133Val) variant causes a missense change. The variant allele was found at a frequency of 0.00403 in 1,614,190 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A133T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (21 hom.)
• Consequence: SLC34A1 NM_003052.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 6.15

Genes affected

SLC34A1 (HGNC:11019): (solute carrier family 34 member 1) Enables sodium:phosphate symporter activity. Involved in several processes, including phosphate ion homeostasis; phosphate ion transport; and response to lead ion. Located in several cellular components, including apical plasma membrane; mitotic spindle; and nuclear speck. Implicated in several diseases, including Fanconi syndrome (multiple); chronic kidney disease; hereditary hypophosphatemic rickets with hypercalciuria; hypophosphatemic nephrolithiasis/osteoporosis 1; and nephrolithiasis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015867203).
• BP6: Variant 5-177386432-C-T is Benign according to our data. Variant chr5-177386432-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 352960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177386432-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00299 (455/152320) while in subpopulation NFE AF= 0.00393 (267/68016). AF 95% confidence interval is 0.00354. There are 2 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC34A1	NM_003052.5	c.398C>T	p.Ala133Val	missense_variant	5/13	ENST00000324417.6
SLC34A1	NM_001167579.2	c.398C>T	p.Ala133Val	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC34A1	ENST00000324417.6	c.398C>T	p.Ala133Val	missense_variant	5/13	1	NM_003052.5	P1
SLC34A1	ENST00000512593.5	c.398C>T	p.Ala133Val	missense_variant	5/9	2
SLC34A1	ENST00000507685.5	n.482C>T		non_coding_transcript_exon_variant	5/10	2

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152202 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00372 AC: 936 AN: 251438 Hom.: 2 AF XY: 0.00389 AC XY: 528 AN XY: 135904

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00774

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00457

Gnomad FIN exome AF: 0.00767

Gnomad NFE exome AF: 0.00389

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00414 AC: 6046 AN: 1461870 Hom.: 21 Cov.: 34 AF XY: 0.00426 AC XY: 3095 AN XY: 727240

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00781

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00511

Gnomad4 FIN exome AF: 0.00831

Gnomad4 NFE exome AF: 0.00417

Gnomad4 OTH exome AF: 0.00338

GnomAD4 genome AF: 0.00299 AC: 455 AN: 152320 Hom.: 2 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74482

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.00393

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00361 Hom.: 2

Bravo AF: 0.00244

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00348 AC: 423

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00415

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16688119, 30778725, 31188746, 28893421, 26787776) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SLC34A1: BS2 -

Nephrocalcinosis Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Sep 08, 2017

- -

Hypophosphatemic nephrolithiasis/osteoporosis 1;C3150652:Fanconi renotubular syndrome 2;C4310473:Hypercalcemia, infantile, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 15, 2022

- -

Hypophosphatemic nephrolithiasis/osteoporosis 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

SLC34A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 13, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.016	T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.61
MVP		0.81
MPC		0.40
ClinPred		0.013	T
GERP RS		5.6
Varity_R		0.66
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs148976897; hg19: chr5-176813433;