NM_003052.5:c.398C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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 Conflicting classifications of pathogenicity (no stars). 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:8

Conservation

PhyloP100: 6.15

Publications

10 publications found

Variant links:

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]

SLC34A1 Gene-Disease associations (from GenCC):

hypercalcemia, infantile, 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
dominant hypophosphatemia with nephrolithiasis or osteoporosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
primary Fanconi syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive infantile hypercalcemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypophosphatemic nephrolithiasis/osteoporosis 1
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Fanconi renotubular syndrome 2
Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

SLC34A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 352960.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC34A1	NM_003052.5 link	c.398C>T	p.Ala133Val	missense_variant	Exon 5 of 13	ENST00000324417.6	NP_003043.3	Q06495-1A0A024R7R9Q86VN6Q7Z725
SLC34A1	NM_001167579.2 link	c.398C>T	p.Ala133Val	missense_variant	Exon 5 of 9		NP_001161051.1	Q06495-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC34A1	ENST00000324417.6 link	c.398C>T	p.Ala133Val	missense_variant	Exon 5 of 13	1	NM_003052.5	ENSP00000321424.4	Q06495-1
SLC34A1	ENST00000512593.5 link	c.398C>T	p.Ala133Val	missense_variant	Exon 5 of 9	2		ENSP00000423022.1	Q06495-2
SLC34A1	ENST00000507685.5 link	n.482C>T		non_coding_transcript_exon_variant	Exon 5 of 10	2
SLC34A1	ENST00000504577.5 link	c.*142C>T		downstream_gene_variant		4		ENSP00000423733.1	D6RCE5

Frequencies

GnomAD3 genomes

AF:

0.00300

AC:

456

AN:

152202

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00372

AC:

936

AN:

251438

AF XY:

0.00389

show subpopulations

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 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.:

Cov.:

AF XY:

0.00426

AC XY:

3095

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33480

American (AMR)

AF:

0.00181

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00781

AC:

204

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00511

AC:

441

AN:

86256

European-Finnish (FIN)

AF:

0.00831

AC:

444

AN:

53410

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00417

AC:

4641

AN:

1112002

Other (OTH)

AF:

0.00338

AC:

204

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

457

913

1370

1826

2283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00299

AC:

455

AN:

152320

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

228

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000625

AC:

AN:

41578

American (AMR)

AF:

0.00242

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00352

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00631

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00393

AC:

267

AN:

68016

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00376

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00348

AC:

423

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC34A1: BS2 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 22, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

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

Uncertain:1Benign:2

Apr 15, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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, BS1 -

Nephrocalcinosis

Pathogenic:1

Sep 08, 2017

Yale Center for Mendelian Genomics, Yale University

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hypophosphatemic nephrolithiasis/osteoporosis 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 13, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

.;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

6.2

PrimateAI

Uncertain

0.73

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

GERP RS

5.6

Varity_R

0.66

gMVP

0.76

Mutation Taster

=43/57

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over