Genetic Variant SLC34A3:p.Gly196Trp (chr9-137233234-G-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_001177316.2(SLC34A3):c.586G>T(p.Gly196Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000843 in 1,422,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G196R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000084 ( 0 hom. )

Consequence

SLC34A3
NM_001177316.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.766

Variant links:

Genes affected

SLC34A3 (HGNC:20305): (solute carrier family 34 member 3) This gene encodes a member of SLC34A transporter family of proteins, and is expressed primarily in the kidney. It is involved in transporting phosphate into cells via sodium cotransport in the renal brush border membrane, and contributes to the maintenance of inorganic phosphate concentration in the kidney. Mutations in this gene are associated with hereditary hypophosphatemic rickets with hypercalciuria. Alternatively spliced transcript variants varying in the 5' UTR have been found for this gene.[provided by RefSeq, Apr 2010]

SLC34A3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001177316.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-137233234-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC34A3	NM_001177316.2 link	c.586G>T	p.Gly196Trp	missense_variant	Exon 7 of 13	ENST00000673835.1	NP_001170787.2	Q8N130

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC34A3	ENST00000673835.1 link	c.586G>T	p.Gly196Trp	missense_variant	Exon 7 of 13		NM_001177316.2	ENSP00000501114.1	Q8N130
SLC34A3	ENST00000361134.2 link	c.586G>T	p.Gly196Trp	missense_variant	Exon 7 of 13	2		ENSP00000355353.2	Q8N130
SLC34A3	ENST00000538474.5 link	c.586G>T	p.Gly196Trp	missense_variant	Exon 7 of 13	5		ENSP00000442397.1	Q8N130
SLC34A3	ENST00000673865.1 link	c.586G>T	p.Gly196Trp	missense_variant	Exon 7 of 10			ENSP00000501101.1	A0A669KB63

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000269

AC:

AN:

185974

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000301

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000843

AC:

AN:

1422966

Hom.:

Cov.:

AF XY:

0.00000851

AC XY:

AN XY:

704890

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32422

American (AMR)

AF:

0.00

AC:

AN:

39830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25512

East Asian (EAS)

AF:

0.00

AC:

AN:

37092

South Asian (SAS)

AF:

0.00

AC:

AN:

82118

European-Finnish (FIN)

AF:

0.000205

AC:

AN:

48882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1092800

Other (OTH)

AF:

0.0000170

AC:

AN:

58712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

D;D

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.95

D;.

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.9

L;L

PhyloP100

0.77

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

D;D

Vest4

0.67

MutPred

0.78

Gain of MoRF binding (P = 0.0868);Gain of MoRF binding (P = 0.0868);

MVP

0.77

MPC

0.24

ClinPred

0.52

GERP RS

-1.3

Varity_R

0.62

gMVP

0.67

Mutation Taster

=41/59

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over