Genetic Variant PLCB4:p.Arg633His (chr20-9409080-G-A) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_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. 14/22 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
NM_001377142.1 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 10.0

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

auriculocondylar syndrome 2
Inheritance: AD, SD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
auriculocondylar syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PLCB4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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-T is described in ClinVar as Pathogenic. ClinVar VariationId is 64692.Status of the report is no_assertion_criteria_provided, 0 stars.

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 VariationId is 31639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377142.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCB4	NM_001377142.1	MANE Select	c.1898G>A	p.Arg633His	missense	Exon 24 of 40	NP_001364071.1	A0A7P0MRI8
PLCB4	NM_001377143.1		c.1898G>A	p.Arg633His	missense	Exon 23 of 39	NP_001364072.1	A0A7P0MRI8
PLCB4	NM_000933.4		c.1862G>A	p.Arg621His	missense	Exon 23 of 39	NP_000924.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCB4	ENST00000378473.9	TSL:1 MANE Select	c.1898G>A	p.Arg633His	missense	Exon 24 of 40	ENSP00000367734.5	A0A7P0MRI8
PLCB4	ENST00000278655.9	TSL:1	c.1808G>A	p.Arg603His	missense	Exon 21 of 36	ENSP00000278655.5	A0A8I5KRP3
PLCB4	ENST00000464199.5	TSL:1	n.1639G>A		non_coding_transcript_exon	Exon 14 of 29

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000535

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Auriculocondylar syndrome 2 (4)

Auriculocondylar syndrome (1)

Auriculocondylar syndrome 1 (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.2

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.4

PhyloP100

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.98

MutPred

0.92

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

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over