rs876661296

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BS1_SupportingBS2

The NM_003052.5(SLC34A1):c.272_292delTCCCCAAGCTGCGCCAGGCTG(p.Val91_Ala97del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 1,614,122 control chromosomes in the GnomAD database, including 439 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.017 ( 24 hom., cov: 32)

Exomes 𝑓: 0.023 ( 415 hom. )

Consequence

SLC34A1
NM_003052.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4B:4

Conservation

PhyloP100: 2.59

Publications

8 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: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_003052.5.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2599/152316) while in subpopulation NFE AF = 0.0266 (1808/68014). AF 95% confidence interval is 0.0256. There are 24 homozygotes in GnomAd4. There are 1263 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 24 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC34A1	NM_003052.5 link	c.272_292delTCCCCAAGCTGCGCCAGGCTG	p.Val91_Ala97del	disruptive_inframe_deletion	Exon 4 of 13	ENST00000324417.6	NP_003043.3
SLC34A1	NM_001167579.2 link	c.272_292delTCCCCAAGCTGCGCCAGGCTG	p.Val91_Ala97del	disruptive_inframe_deletion	Exon 4 of 9		NP_001161051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SLC34A1	ENST00000324417.6 link	c.272_292delTCCCCAAGCTGCGCCAGGCTG	p.Val91_Ala97del	disruptive_inframe_deletion	Exon 4 of 13	1	NM_003052.5	ENSP00000321424.4
SLC34A1	ENST00000512593.5 link	c.272_292delTCCCCAAGCTGCGCCAGGCTG	p.Val91_Ala97del	disruptive_inframe_deletion	Exon 4 of 9	2		ENSP00000423022.1
SLC34A1	ENST00000504577.5 link	c.272_292delTCCCCAAGCTGCGCCAGGCTG	p.Val91_Ala97del	disruptive_inframe_deletion	Exon 4 of 4	4		ENSP00000423733.1
SLC34A1	ENST00000507685.5 link	n.356_376delTCCCCAAGCTGCGCCAGGCTG		non_coding_transcript_exon_variant	Exon 4 of 10	2

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2600

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00463

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.00988

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.0305

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0266

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.0168

AC:

4220

AN:

251174

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.00541

Gnomad ASJ exome

AF:

0.00914

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0278

Gnomad NFE exome

AF:

0.0253

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0225

AC:

32895

AN:

1461806

Hom.:

415

AF XY:

0.0223

AC XY:

16228

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00346

AC:

116

AN:

33480

American (AMR)

AF:

0.00570

AC:

255

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00884

AC:

231

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0106

AC:

910

AN:

86254

European-Finnish (FIN)

AF:

0.0285

AC:

1519

AN:

53390

Middle Eastern (MID)

AF:

0.00693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0258

AC:

28680

AN:

1111964

Other (OTH)

AF:

0.0189

AC:

1143

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.409

Heterozygous variant carriers

2124

4247

6371

8494

10618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1058

2116

3174

4232

5290

<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:

0.0171

AC:

2599

AN:

152316

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1263

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00462

AC:

192

AN:

41574

American (AMR)

AF:

0.00986

AC:

151

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00787

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0305

AC:

324

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0266

AC:

1808

AN:

68014

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

133

266

399

532

665

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0192

Hom.:

Bravo

AF:

0.0143

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0211

EpiControl

AF:

0.0219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercalcemia, infantile, 2

Pathogenic:4Uncertain:1Benign:1

Mar 08, 2024

Molecular Genetics Laboratory, Biobizkaia Health Research Institute

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

NM_003052.4:c.272_292del in the SLC34A1 gene has an allele frequency of 0.025 in European (non-Finnish) subpopulation in the gnomAD database, including 41 homozygous occurrences. However, considering the prevalence of hypercalcemia in the general population is approximately 1% to 2% (NCBI Bookshelf, Hypercalcemia), and it is not lethal, we decided not to take the allele frequency as a strong benign evidence. This variant was identified in homozygous state in a girl who presented with incidental nephrocalcinosis and polyuria (PMID: 26047794). Functional analyses confirmed the impaired trafficking of NaPi-IIa-91del7 in HEK293 cells while phosphate uptake in the Xenopus oocyte system was largely preserved (PMID: 26047794). We interpret it as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3, PM3, PM4.

Oct 06, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jan 02, 2024

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 31, 2021

MK Azim Lab, Mohammad Ali Jinnah University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 31, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

not provided

Uncertain:2Benign:2

Jan 11, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2, PM3, PM4, PS3_supporting, PS4_moderate

Feb 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26047794, 29959532, 25296721, 16688119, 27378183, 28470390)

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC34A1: PM3, PM4, PM2:Supporting, PS3:Supporting, BS2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Uncertain:1Benign:1

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: PS3, BS1

Oct 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.6

Mutation Taster

=166/34

polymorphism (auto)

(source)

Splicing

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