chr5-177385815-G-A

Variant names:

• chr5-177385815-G-A
• rs112528230
• NM_003052.5:c.74G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_003052.5(SLC34A1):​c.74G>A​(p.Arg25Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,613,470 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: SLC34A1 NM_003052.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.995

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03405139).
• BP6: Variant 5-177385815-G-A is Benign according to our data. Variant chr5-177385815-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 904291.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC34A1	NM_003052.5	c.74G>A	p.Arg25Gln	missense_variant	Exon 2 of 13	ENST00000324417.6	NP_003043.3
SLC34A1	NM_001167579.2	c.74G>A	p.Arg25Gln	missense_variant	Exon 2 of 9		NP_001161051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC34A1	ENST00000324417.6	c.74G>A	p.Arg25Gln	missense_variant	Exon 2 of 13	1	NM_003052.5	ENSP00000321424.4
SLC34A1	ENST00000512593.5	c.74G>A	p.Arg25Gln	missense_variant	Exon 2 of 9	2		ENSP00000423022.1
SLC34A1	ENST00000504577.5	c.74G>A	p.Arg25Gln	missense_variant	Exon 2 of 4	4		ENSP00000423733.1
SLC34A1	ENST00000507685.5	n.158G>A		non_coding_transcript_exon_variant	Exon 2 of 10	2

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000194 AC: 48 AN: 247024 Hom.: 0 AF XY: 0.000194 AC XY: 26 AN XY: 133720

Gnomad AFR exome AF: 0.000685

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000273

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000145

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000171 AC: 250 AN: 1461210 Hom.: 1 Cov.: 33 AF XY: 0.000190 AC XY: 138 AN XY: 726866

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000279

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74452

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000190 Hom.: 0

Bravo AF: 0.000325

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Sep 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 25 of the SLC34A1 protein (p.Arg25Gln). This variant is present in population databases (rs112528230, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with SLC34A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 904291). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Jan 16, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

Hypophosphatemic nephrolithiasis/osteoporosis 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.14
DANN	Benign	0.96
DEOGEN2	Benign	0.16	.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.85	T;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.080	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.56	.;.;P
Vest4		0.32, 0.29
MVP		0.26
MPC		0.085
ClinPred		0.0058	T
GERP RS		-5.4
Varity_R		0.028
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs112528230; hg19: chr5-176812816; COSMIC: COSV60997735; COSMIC: COSV60997735;