Variant 4-25662703-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_006424.3(SLC34A2):c.113-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

SLC34A2
NM_006424.3 splice_acceptor

Scores

Splicing: ADA: 0.9987

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.221

Variant links:

Genes affected

SLC34A2 (HGNC:11020): (solute carrier family 34 member 2) The protein encoded by this gene is a pH-sensitive sodium-dependent phosphate transporter. Phosphate uptake is increased at lower pH. Defects in this gene are a cause of pulmonary alveolar microlithiasis. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, May 2010]

SLC34A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0660878 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.7, offset of 3, new splice context is: ccttttgcttgtttcggcAGata. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-25662703-A-G is Pathogenic according to our data. Variant chr4-25662703-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 981832.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
SLC34A2	NM_006424.3 linkuse as main transcript	c.113-2A>G	splice_acceptor_variant	ENST00000382051.8	NP_006415.3
SLC34A2	NM_001177998.2 linkuse as main transcript	c.113-5A>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001171469.2
SLC34A2	NM_001177999.2 linkuse as main transcript	c.113-5A>G	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001171470.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC34A2	ENST00000382051.8 linkuse as main transcript	c.113-2A>G		splice_acceptor_variant		1	NM_006424.3	ENSP00000371483	P4	O95436-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Molecular Oncology Research Center, Barretos Cancer Hospital

Aug 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.96

CADD

Benign

9.4

DANN

Benign

0.41

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.0078

MutationTaster

Benign

1.0

N;N;N

GERP RS

-4.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.48

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.99

Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over