5-177386473-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_003052.5(SLC34A1):​c.439G>A​(p.Val147Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SLC34A1
NM_003052.5 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 6.78
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a transmembrane_region Helical; Name=M2 (size 17) in uniprot entity NPT2A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003052.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC34A1NM_003052.5 linkuse as main transcriptc.439G>A p.Val147Met missense_variant 5/13 ENST00000324417.6 NP_003043.3
SLC34A1NM_001167579.2 linkuse as main transcriptc.439G>A p.Val147Met missense_variant 5/9 NP_001161051.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC34A1ENST00000324417.6 linkuse as main transcriptc.439G>A p.Val147Met missense_variant 5/131 NM_003052.5 ENSP00000321424 P1Q06495-1
SLC34A1ENST00000512593.5 linkuse as main transcriptc.439G>A p.Val147Met missense_variant 5/92 ENSP00000423022 Q06495-2
SLC34A1ENST00000507685.5 linkuse as main transcriptn.523G>A non_coding_transcript_exon_variant 5/102

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
32
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251438
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461862
Hom.:
0
Cov.:
34
AF XY:
0.00000275
AC XY:
2
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hypophosphatemic nephrolithiasis/osteoporosis 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 26, 2002- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 12, 2022Experimental studies have shown that this missense change affects SLC34A1 function (PMID: 12324554, 14672348). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 12932). This missense change has been observed in individual(s) with demineralization and hypophosphatemia (PMID: 12324554). This variant is present in population databases (rs121918611, gnomAD 0.002%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 147 of the SLC34A1 protein (p.Val147Met). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.72
.;D
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.054
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Uncertain
0.70
D
MutationAssessor
Uncertain
2.4
M;M
MutationTaster
Benign
1.0
A;A
PrimateAI
Uncertain
0.79
T
PROVEAN
Benign
-1.6
N;N
REVEL
Pathogenic
0.79
Sift
Uncertain
0.016
D;D
Sift4G
Uncertain
0.040
D;D
Polyphen
0.97
.;D
Vest4
0.80
MutPred
0.85
Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP
0.84
MPC
0.34
ClinPred
0.94
D
GERP RS
5.6
Varity_R
0.50
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

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

Other links and lift over

dbSNP: rs121918611; hg19: chr5-176813474; API