rs111532084

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001177316.2(SLC34A3):c.175+123C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 989,004 control chromosomes in the GnomAD database, including 523 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 60 hom., cov: 33)

Exomes 𝑓: 0.029 ( 463 hom. )

Consequence

SLC34A3
NM_001177316.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.38

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 9-137232284-C-T is Benign according to our data. Variant chr9-137232284-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 496510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0236 (3598/152306) while in subpopulation NFE AF = 0.0368 (2501/68012). AF 95% confidence interval is 0.0356. There are 60 homozygotes in GnomAd4. There are 1670 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 60 SD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC34A3	NM_001177316.2 link	c.175+123C>T		intron_variant	Intron 3 of 12	ENST00000673835.1	NP_001170787.2	Q8N130

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC34A3	ENST00000673835.1 link	c.175+123C>T		intron_variant	Intron 3 of 12		NM_001177316.2	ENSP00000501114.1		Q8N130

Frequencies

GnomAD3 genomes

AF:

0.0236

AC:

3596

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00613

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.0438

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0232

Gnomad FIN

AF:

0.0156

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0368

Gnomad OTH

AF:

0.0282

GnomAD4 exome

AF:

0.0290

AC:

24258

AN:

836698

Hom.:

463

AF XY:

0.0292

AC XY:

12656

AN XY:

433256

show subpopulations

African (AFR)

AF:

0.00555

AC:

118

AN:

21244

American (AMR)

AF:

0.0180

AC:

678

AN:

37698

Ashkenazi Jewish (ASJ)

AF:

0.0327

AC:

639

AN:

19516

East Asian (EAS)

AF:

0.0000562

AC:

AN:

35596

South Asian (SAS)

AF:

0.0221

AC:

1480

AN:

67082

European-Finnish (FIN)

AF:

0.0190

AC:

718

AN:

37698

Middle Eastern (MID)

AF:

0.0223

AC:

AN:

3006

European-Non Finnish (NFE)

AF:

0.0338

AC:

19450

AN:

575380

Other (OTH)

AF:

0.0280

AC:

1106

AN:

39478

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1322

2644

3966

5288

6610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

458

916

1374

1832

2290

<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

AF:

0.0236

AC:

3598

AN:

152306

Hom.:

Cov.:

AF XY:

0.0224

AC XY:

1670

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00611

AC:

254

AN:

41570

American (AMR)

AF:

0.0196

AC:

300

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0438

AC:

152

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.0234

AC:

113

AN:

4828

European-Finnish (FIN)

AF:

0.0156

AC:

166

AN:

10622

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0368

AC:

2501

AN:

68012

Other (OTH)

AF:

0.0279

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

177

355

532

710

887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0297

Hom.:

Bravo

AF:

0.0231

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 16, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The SLC34A3 c.175+123C>T variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in controls (from 1000 Gs) with an allele frequency of 74/5008 (1/68), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic SLC34A3 variant of 1/894 (0.001118), suggesting this variant is likely a benign polymorphism. The variant of interest was reported in one HHRH patient, but the authors considered the variant of interest a polymorphism. Additionally, one internal LCA specimen carried this variant and was homozygous for a pathogenic SLC34A3 variant, c.560+27_561-38del30. c.175+123C>T has not been reported in affected individuals or classified by other clinical labs. Therefore, taking all available lines of evidence into consideration and the high allele frequency in the general population, the variant of interest has been classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.9

(source)

DANN

Benign

0.49

PhyloP100

-1.4

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over