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rs397514771

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP2PP3_StrongPP5

The NM_001377142.1(PLCB4):​c.1079A>T​(p.Asp360Val) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D360N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PLCB4
NM_001377142.1 missense

Scores

15
2
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.30
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr20-9387476-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 64694.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, PLCB4
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.964
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 20-9387477-A-T is Pathogenic according to our data. Variant chr20-9387477-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 64695.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PLCB4NM_001377142.1 linkuse as main transcriptc.1079A>T p.Asp360Val missense_variant 15/40 ENST00000378473.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PLCB4ENST00000378473.9 linkuse as main transcriptc.1079A>T p.Asp360Val missense_variant 15/401 NM_001377142.1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1430956
Hom.:
0
Cov.:
25
AF XY:
0.00
AC XY:
0
AN XY:
713576
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Auriculocondylar syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
32
DANN
Uncertain
0.99
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;.;.;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D
MetaSVM
Uncertain
0.63
D
MutationAssessor
Pathogenic
3.3
M;M;M;M;M
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-8.7
D;D;N;D;D
REVEL
Pathogenic
0.77
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;D;D
Vest4
0.99
MutPred
0.85
Loss of catalytic residue at D360 (P = 0.0463);Loss of catalytic residue at D360 (P = 0.0463);Loss of catalytic residue at D360 (P = 0.0463);Loss of catalytic residue at D360 (P = 0.0463);Loss of catalytic residue at D360 (P = 0.0463);
MVP
0.93
MPC
2.0
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.97
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs397514771; hg19: chr20-9368124; API