rs148976897

Variant names:

• chr5-177386432-C-T
• rs148976897
• NM_003052.5:c.398C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003052.5(SLC34A1):​c.398C>T​(p.Ala133Val) variant causes a missense change. The variant allele was found at a frequency of 0.00403 in 1,614,190 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A133T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (21 hom.)
• Consequence: SLC34A1 NM_003052.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:8
• Conservation: PhyloP100: 6.15
• Publications: 10 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: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
• hypophosphatemic nephrolithiasis/osteoporosis 1

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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
• Fanconi renotubular syndrome 2

  Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015867203).
• BP6: Variant 5-177386432-C-T is Benign according to our data. Variant chr5-177386432-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 352960.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003052.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC34A1	NM_003052.5	MANE Select	c.398C>T	p.Ala133Val	missense	Exon 5 of 13	NP_003043.3
	SLC34A1	NM_001167579.2		c.398C>T	p.Ala133Val	missense	Exon 5 of 9	NP_001161051.1	Q06495-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC34A1	ENST00000324417.6	TSL:1 MANE Select	c.398C>T	p.Ala133Val	missense	Exon 5 of 13	ENSP00000321424.4	Q06495-1
	SLC34A1	ENST00000872468.1		c.398C>T	p.Ala133Val	missense	Exon 5 of 13	ENSP00000542527.1
	SLC34A1	ENST00000512593.5	TSL:2	c.398C>T	p.Ala133Val	missense	Exon 5 of 9	ENSP00000423022.1	Q06495-2

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152202 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00372 AC: 936 AN: 251438 AF XY: 0.00389

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.00774

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00767

Gnomad NFE exome AF: 0.00389

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00414 AC: 6046 AN: 1461870 Hom.: 21 Cov.: 34 AF XY: 0.00426 AC XY: 3095 AN XY: 727240

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00181 AC: 81 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00781 AC: 204 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00511 AC: 441 AN: 86256

European-Finnish (FIN) AF: 0.00831 AC: 444 AN: 53410

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00417 AC: 4641 AN: 1112002

Other (OTH) AF: 0.00338 AC: 204 AN: 60396

GnomAD4 genome AF: 0.00299 AC: 455 AN: 152320 Hom.: 2 Cov.: 32 AF XY: 0.00306 AC XY: 228 AN XY: 74482

African (AFR) AF: 0.000625 AC: 26 AN: 41578

American (AMR) AF: 0.00242 AC: 37 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4828

European-Finnish (FIN) AF: 0.00631 AC: 67 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00393 AC: 267 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00376 Hom.: 6

Bravo AF: 0.00244

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00348 AC: 423

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	Hypophosphatemic nephrolithiasis/osteoporosis 1;C3150652:Fanconi renotubular syndrome 2;C4310473:Hypercalcemia, infantile, 2 (3)
-	-	1	Hypophosphatemic nephrolithiasis/osteoporosis 1 (1)
1	-	-	Nephrocalcinosis (1)
-	-	1	SLC34A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.81
MPC		0.40
ClinPred		0.013	T
GERP RS		5.6
Varity_R		0.66
gMVP		0.76
Mutation Taster		=43/57	disease causing

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

Other links and lift over

dbSNP: rs148976897; hg19: chr5-176813433;