rs201304511

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_003052.5(SLC34A1):​c.644+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000077 in 1,610,972 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

SLC34A1
NM_003052.5 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:4

Conservation

PhyloP100: 9.89
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 Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-177387874-G-A is Pathogenic according to our data. Variant chr5-177387874-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 234926.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177387874-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC34A1NM_003052.5 linkuse as main transcriptc.644+1G>A splice_donor_variant, intron_variant ENST00000324417.6 NP_003043.3 Q06495-1A0A024R7R9Q86VN6Q7Z725
SLC34A1NM_001167579.2 linkuse as main transcriptc.644+1G>A splice_donor_variant, intron_variant NP_001161051.1 Q06495-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC34A1ENST00000324417.6 linkuse as main transcriptc.644+1G>A splice_donor_variant, intron_variant 1 NM_003052.5 ENSP00000321424.4 Q06495-1
SLC34A1ENST00000512593.5 linkuse as main transcriptc.644+1G>A splice_donor_variant, intron_variant 2 ENSP00000423022.1 Q06495-2
SLC34A1ENST00000507685.5 linkuse as main transcriptn.729G>A non_coding_transcript_exon_variant 6/102

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
151916
Hom.:
0
Cov.:
31
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:
0.0000883
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000777
AC:
19
AN:
244652
Hom.:
0
AF XY:
0.0000674
AC XY:
9
AN XY:
133572
show subpopulations
Gnomad AFR exome
AF:
0.000130
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000476
Gnomad NFE exome
AF:
0.000137
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000809
AC:
118
AN:
1459056
Hom.:
0
Cov.:
44
AF XY:
0.0000827
AC XY:
60
AN XY:
725802
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000192
Gnomad4 NFE exome
AF:
0.0000963
Gnomad4 OTH exome
AF:
0.0000995
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
151916
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74196
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:
0.0000883
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000133
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000660
AC:
8

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Nephrocalcinosis;C0392525:Nephrolithiasis Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyYale Center for Mendelian Genomics, Yale UniversitySep 08, 2017- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 09, 2023This sequence change affects a donor splice site in intron 6 of the SLC34A1 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 SLC34A1 are known to be pathogenic (PMID: 26047794). This variant is present in population databases (rs201304511, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with clinical features of infantile hypercalcemia (PMID: 26047794, 28893421, 29959532). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 234926). 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. -
SLC34A1-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 04, 2024The SLC34A1 c.644+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the homozygous and compound heterozygous states in individuals with infantile hypercalcemia (Schlingmann et al. 2016. PubMed ID: 26047794; Daga et al. 2017. PubMed ID: 28893421; Hureaux et al. 2018. PubMed ID: 29959532). This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt consensus splice donor sites in SLC34A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Hypercalcemia, infantile, 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 06, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
5.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.94
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.94
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.

Other links and lift over

dbSNP: rs201304511; hg19: chr5-176814875; API