20-9409080-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_001377142.1(PLCB4):​c.1898G>T​(p.Arg633Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,824 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PLCB4
NM_001377142.1 missense

Scores

14
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 10.0
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 Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the PLCB4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 3.5718 (above the threshold of 3.09). Trascript score misZ: 3.2758 (above the threshold of 3.09). GenCC associations: The gene is linked to auriculocondylar syndrome 1, auriculocondylar syndrome, auriculocondylar syndrome 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
Variant 20-9409080-G-T is Pathogenic according to our data. Variant chr20-9409080-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 64692.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PLCB4NM_001377142.1 linkc.1898G>T p.Arg633Leu missense_variant Exon 24 of 40 ENST00000378473.9 NP_001364071.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PLCB4ENST00000378473.9 linkc.1898G>T p.Arg633Leu missense_variant Exon 24 of 40 1 NM_001377142.1 ENSP00000367734.5 A0A7P0MRI8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1456824
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
724574
show subpopulations
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:
9.01e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

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
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
.;D;.;D;.
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;.;.;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
4.0
.;H;.;H;H
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-6.9
D;D;D;D;D
REVEL
Pathogenic
0.72
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 = 0.0027);.;Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);
MVP
0.98
MPC
1.9
ClinPred
1.0
D
GERP RS
6.2
Varity_R
0.95
gMVP
1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397514481; hg19: chr20-9389727; API