rs397514481

Positions:

• chr20-9409080-G-A
• chr20-9409080-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000378473.9(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R633L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCB4 ENST00000378473.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-9409079-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 31640.Status of the report is criteria_provided_single_submitter, 1 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, 0.98
• 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/exons	MANE	Protein	UniProt
PLCB4	NM_001377142.1	c.1898G>A	p.Arg633His	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	c.1898G>A	p.Arg633His	missense_variant	24/40	1	NM_001377142.1	ENSP00000367734

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Auriculocondylar syndrome 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 28, 2023	Criteria applied: PM5_STR,PS2_MOD,PS4_MOD,PM1,PM2_SUP,PP3,PP4 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2013	- -
Pathogenic, no assertion criteria provided	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	research	Tammimies Lab, Karolinska Institutet	Jan 05, 2023	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2017

- -

Auriculocondylar syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 19, 2019

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

Pathogenic, criteria provided, single submitter

research

University of Washington Center for Mendelian Genomics, University of Washington

Sep 17, 2012

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2022

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	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	.;D;.;D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;.;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	.;H;.;H;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
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	D
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

Other links and lift over

dbSNP: rs397514481; hg19: chr20-9389727; COSMIC: COSV53800524;