Variant 20-9409080-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP2PP3_StrongPP5

The ENST00000378473.9(PLCB4):c.1898G>T(p.Arg633Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R633H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PLCB4
ENST00000378473.9 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

PLCB4 (HGNC:9059): (phospholipase C beta 4) The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals in the retina. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2010]

PLCB4 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-9409080-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 31639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PLCB4. . Gene score misZ 3.5718 (greater than the threshold 3.09). Trascript score misZ 3.2758 (greater than threshold 3.09). GenCC has associacion of gene with auriculocondylar syndrome 1, auriculocondylar syndrome, auriculocondylar syndrome 2.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 20-9409080-G-T is Pathogenic according to our data. Variant chr20-9409080-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 64692.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB4	NM_001377142.1 linkuse as main transcript	c.1898G>T	p.Arg633Leu	missense_variant	24/40	ENST00000378473.9	NP_001364071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCB4	ENST00000378473.9 linkuse as main transcript	c.1898G>T	p.Arg633Leu	missense_variant	24/40	1	NM_001377142.1	ENSP00000367734

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456824

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724574

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Auriculocondylar syndrome 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

.;D;.;D;.

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;.;.;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.0

.;H;.;H;H

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.9

D;D;D;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

.;D;.;D;D

Vest4

0.98

MutPred

0.92

.;Loss of MoRF binding (P = 0.0027);.;Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);

MVP

0.98

MPC

1.9

ClinPred

1.0

GERP RS

6.2

Varity_R

0.95

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

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