dbSNP rs397514482: PLCB4:p.Arg633Ser (chr20-9409079-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001377142.1(PLCB4):c.1897C>A(p.Arg633Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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

Not reported in ClinVar

Conservation

PhyloP100: 6.10

Publications

7 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: AR, AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, 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: Likely_pathogenic. The variant received 8 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, 0.982

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.1897C>A	p.Arg633Ser	missense	Exon 24 of 40	NP_001364071.1	A0A7P0MRI8
PLCB4	NM_001377143.1		c.1897C>A	p.Arg633Ser	missense	Exon 23 of 39	NP_001364072.1	A0A7P0MRI8
PLCB4	NM_000933.4		c.1861C>A	p.Arg621Ser	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.1897C>A	p.Arg633Ser	missense	Exon 24 of 40	ENSP00000367734.5	A0A7P0MRI8
PLCB4	ENST00000278655.9	TSL:1	c.1807C>A	p.Arg603Ser	missense	Exon 21 of 36	ENSP00000278655.5	A0A8I5KRP3
PLCB4	ENST00000464199.5	TSL:1	n.1638C>A		non_coding_transcript_exon	Exon 14 of 29

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000405

AC:

AN:

246856

AF XY:

0.00000750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.4

PhyloP100

6.1

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.99

MutPred

0.91

Loss of MoRF binding (P = 0.0099)

MVP

0.97

MPC

1.8

ClinPred

1.0

GERP RS

6.2

Varity_R

0.98

gMVP

1.0

Mutation Taster

=4/96

disease causing

(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