rs1554095568

Variant names:

• chr5-177388370-C-T
• rs1554095568
• NM_003052.5:c.934C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003052.5(SLC34A1):​c.934C>T​(p.Gln312*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC34A1 NM_003052.5 stop_gained, splice_region
• Scores: Splicing: ADA: 0.005653
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.841
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-177388370-C-T is Pathogenic according to our data. Variant chr5-177388370-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 433538.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC34A1	NM_003052.5	c.934C>T	p.Gln312*	stop_gained, splice_region_variant	Exon 8 of 13	ENST00000324417.6	NP_003043.3
SLC34A1	NM_001167579.2	c.934C>T	p.Gln312*	stop_gained, splice_region_variant	Exon 8 of 9		NP_001161051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC34A1	ENST00000324417.6	c.934C>T	p.Gln312*	stop_gained, splice_region_variant	Exon 8 of 13	1	NM_003052.5	ENSP00000321424.4
SLC34A1	ENST00000512593.5	c.934C>T	p.Gln312*	stop_gained, splice_region_variant	Exon 8 of 9	2		ENSP00000423022.1
SLC34A1	ENST00000507685.5	n.1225C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypophosphatemic nephrolithiasis/osteoporosis 1 Pathogenic:1

Aug 11, 2017

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Benign	0.90
Eigen	Benign	0.11
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.50	N
PhyloP100		0.84
Vest4		0.41
GERP RS		1.4
Mutation Taster		=17/183	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0057
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1554095568; hg19: chr5-176815371;