Variant 20-9409086-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_001377142.1(PLCB4):c.1904A>G(p.Tyr635Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PLCB4
NM_001377142.1 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.32

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 Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the PLCB4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 3.5718 (above the threshold of 3.09). Trascript score misZ: 3.2758 (above the threshold of 3.09). GenCC associations: The gene is linked to auriculocondylar syndrome 1, auriculocondylar syndrome, auriculocondylar syndrome 2.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 20-9409086-A-G is Pathogenic according to our data. Variant chr20-9409086-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 31637.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-9409086-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB4	NM_001377142.1 link	c.1904A>G	p.Tyr635Cys	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 link	c.1904A>G	p.Tyr635Cys	missense_variant	24/40	1	NM_001377142.1	ENSP00000367734.5		A0A7P0MRI8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Auriculocondylar syndrome 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 04, 2012

- -

Auriculocondylar syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

University of Washington Center for Mendelian Genomics, University of Washington

Sep 17, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

.;D;.;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;.;.;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.0

.;H;.;H;H

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-9.0

D;D;.;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

.;D;.;D;D

Vest4

0.95

MutPred

0.87

.;Loss of catalytic residue at I622 (P = 0.0561);.;Loss of catalytic residue at I622 (P = 0.0561);Loss of catalytic residue at I622 (P = 0.0561);

MVP

0.97

MPC

1.9

ClinPred

1.0

GERP RS

6.2

Varity_R

0.94

gMVP

0.99

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

Other links and lift over