Genetic Variant NM_001377142.1:c.1904A>G (chr20-9409086-A-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_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. 13/22 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

Publications

6 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, AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics
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 10 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_001377142.1

PM2

Very rare variant in population databases, with high coverage;

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 VariationId is 31637.Status of the report is criteria_provided_single_submitter, 1 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
PLCB4	NM_001377142.1	MANE Select	c.1904A>G	p.Tyr635Cys	missense	Exon 24 of 40	NP_001364071.1
PLCB4	NM_001377143.1		c.1904A>G	p.Tyr635Cys	missense	Exon 23 of 39	NP_001364072.1
PLCB4	NM_000933.4		c.1868A>G	p.Tyr623Cys	missense	Exon 23 of 39	NP_000924.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCB4	ENST00000378473.9	TSL:1 MANE Select	c.1904A>G	p.Tyr635Cys	missense	Exon 24 of 40	ENSP00000367734.5
PLCB4	ENST00000278655.9	TSL:1	c.1814A>G	p.Tyr605Cys	missense	Exon 21 of 36	ENSP00000278655.5
PLCB4	ENST00000464199.5	TSL:1	n.1645A>G		non_coding_transcript_exon	Exon 14 of 29

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Auriculocondylar syndrome 2

Pathogenic:1

May 04, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.0

PhyloP100

9.3

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-9.0

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.87

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

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over