Genetic Variant NM_001177316.2:c.539G>A (chr9-137233094-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001177316.2(SLC34A3):c.539G>A(p.Gly180Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,770 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. G180A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC34A3
NM_001177316.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.69

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hereditary hypophosphatemic rickets with hypercalciuria
Inheritance: SD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

SLC34A3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.784

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177316.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC34A3	NM_001177316.2	MANE Select	c.539G>A	p.Gly180Glu	missense	Exon 6 of 13	NP_001170787.2
SLC34A3	NM_001177317.2		c.539G>A	p.Gly180Glu	missense	Exon 6 of 13	NP_001170788.2
SLC34A3	NM_080877.3		c.539G>A	p.Gly180Glu	missense	Exon 6 of 13	NP_543153.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC34A3	ENST00000673835.1	MANE Select	c.539G>A	p.Gly180Glu	missense	Exon 6 of 13	ENSP00000501114.1
SLC34A3	ENST00000361134.2	TSL:2	c.539G>A	p.Gly180Glu	missense	Exon 6 of 13	ENSP00000355353.2
SLC34A3	ENST00000538474.5	TSL:5	c.539G>A	p.Gly180Glu	missense	Exon 6 of 13	ENSP00000442397.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458770

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52160

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4488

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111830

Other (OTH)

AF:

0.00

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.90

MutationAssessor

Pathogenic

3.1

PhyloP100

6.7

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.6

REVEL

Benign

0.21

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.69

MutPred

0.46

Gain of solvent accessibility (P = 0.024)

MVP

0.64

MPC

0.27

ClinPred

0.99

GERP RS

3.6

Varity_R

0.60

gMVP

0.57

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over