Variant rs397514481 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_001377142.1(PLCB4):c.1898G>A(p.Arg633His) 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. 13/21 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, multiple submitters, no conflicts P:8

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 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 20-9409080-G-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB4	NM_001377142.1 link	c.1898G>A	p.Arg633His	missense_variant	Exon 24 of 40	ENST00000378473.9	NP_001364071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCB4	ENST00000378473.9 link	c.1898G>A	p.Arg633His	missense_variant	Exon 24 of 40	1	NM_001377142.1	ENSP00000367734.5		A0A7P0MRI8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Auriculocondylar syndrome 2

Pathogenic:4

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 05, 2023

Tammimies Lab, Karolinska Institutet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 28, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM5_STR,PS2_MOD,PS4_MOD,PM1,PM2_SUP,PP3,PP4 -

Dec 30, 2017

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Inborn genetic diseases

Pathogenic:1

Sep 07, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Auriculocondylar syndrome

Pathogenic:1

Dec 19, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PLCB4 c.1862G>A (p.Arg621His) variant is a missense variant. Across a selection of the available literature, the p.Arg621His variant has been identified in a heterozygous state in at least seven individuals of a multi-generational family segregating with auriculocondylar syndrome (ACS), and in one sporadic case of ACS, in which the variant occurred in a de novo state (Rieder et al. 2012; Gordon et al. 2013). The p.Arg621His variant was not found in 10758 control alleles and is not reported in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare (Rieder et al. 2012). The p.Arg621His variant is highly conserved through evolution and is located in a catalytic domain of the PCLB4 protein in a region described as a hotspot for missense variation associated with ACS (Gordon et al. 2013). Additionally, at least two more missense variants with different amino acid alterations at the Arg61 residue have been reported in the literature in affected individuals (Gordon et al. 2013). Based on the collective evidence and application of the ACMG criteria, the p.Arg621His variant is classified as pathogenic for auriculocondylar syndrome. -

Auriculocondylar syndrome 1

Pathogenic:1

Sep 17, 2012

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Pathogenic:1

Aug 30, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23315542, 33131036, 32201334, 35170830, 22560091) -

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

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

.;D;.;D;.

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.2

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;.;.;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.4

.;H;.;H;H

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.9

D;D;D;D;D

REVEL

Pathogenic

0.73

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 = 0.0073);.;Loss of MoRF binding (P = 0.0073);Loss of MoRF binding (P = 0.0073);

MVP

0.98

MPC

1.9

ClinPred

1.0

GERP RS

6.2

Varity_R

0.91

gMVP

0.98

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

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