rs5030873

chr5-177388123-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003052.5(SLC34A1):c.774T>C(p.His258=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,864 control chromosomes in the GnomAD database, including 79,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5971 hom., cov: 32)
  • Exomes 𝑓: 0.31 (73377 hom.)
• Consequence: SLC34A1 NM_003052.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.89

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-177388123-T-C is Benign according to our data. Variant chr5-177388123-T-C is described in ClinVar as [Benign]. Clinvar id is 352965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177388123-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC34A1	NM_003052.5	c.774T>C	p.His258=	synonymous_variant	7/13	ENST00000324417.6
SLC34A1	NM_001167579.2	c.774T>C	p.His258=	synonymous_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC34A1	ENST00000324417.6	c.774T>C	p.His258=	synonymous_variant	7/13	1	NM_003052.5	P1
SLC34A1	ENST00000512593.5	c.774T>C	p.His258=	synonymous_variant	7/9	2
SLC34A1	ENST00000507685.5	n.978T>C		non_coding_transcript_exon_variant	6/10	2

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38256 AN: 151972 Hom.: 5972 Cov.: 32

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.259

GnomAD3 exomes AF: 0.295 AC: 74017 AN: 251256 Hom.: 11978 AF XY: 0.309 AC XY: 41967 AN XY: 135812

Gnomad AFR exome AF: 0.0684

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.308

Gnomad EAS exome AF: 0.224

Gnomad SAS exome AF: 0.366

Gnomad FIN exome AF: 0.409

Gnomad NFE exome AF: 0.323

Gnomad OTH exome AF: 0.315

GnomAD4 exome AF: 0.311 AC: 454998 AN: 1461774 Hom.: 73377 Cov.: 55 AF XY: 0.314 AC XY: 228476 AN XY: 727184

Gnomad4 AFR exome AF: 0.0631

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.309

Gnomad4 EAS exome AF: 0.271

Gnomad4 SAS exome AF: 0.367

Gnomad4 FIN exome AF: 0.405

Gnomad4 NFE exome AF: 0.316

Gnomad4 OTH exome AF: 0.295

GnomAD4 genome AF: 0.252 AC: 38256 AN: 152090 Hom.: 5971 Cov.: 32 AF XY: 0.258 AC XY: 19159 AN XY: 74338

Gnomad4 AFR AF: 0.0742

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.305

Gnomad4 EAS AF: 0.224

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.260

Alfa AF: 0.286 Hom.: 2974

Bravo AF: 0.229

Asia WGS AF: 0.290 AC: 1013 AN: 3478

EpiCase AF: 0.325

EpiControl AF: 0.328

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.His258His in exon 7 of SLC34A1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 41.15% (2715/6598) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs5030873). -

Hypophosphatemic nephrolithiasis/osteoporosis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -

Fanconi renotubular syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Hypercalcemia, infantile, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.028
Dann	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs5030873; hg19: chr5-176815124; COSMIC: COSV60997900; COSMIC: COSV60997900;