rs193921109

Positions:

• chr20-9362934-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000378473.9(PLCB4):​c.408C>A​(p.Phe136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLCB4 ENST00000378473.9 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PLCB4. . Gene score misZ 3.5718 (greater than the threshold 3.09). Trascript score misZ 3.2758 (greater than threshold 3.09). GenCC has associacion of gene with auriculocondylar syndrome 1, auriculocondylar syndrome, auriculocondylar syndrome 2.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4029398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB4	NM_001377142.1	c.408C>A	p.Phe136Leu	missense_variant	8/40	ENST00000378473.9	NP_001364071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCB4	ENST00000378473.9	c.408C>A	p.Phe136Leu	missense_variant	8/40	1	NM_001377142.1	ENSP00000367734

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.18	.;T;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D;.;.;D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.23	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.19	N;N;.;N;N
REVEL	Benign	0.22
Sift	Benign	0.86	T;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.92, 0.0070	.;P;.;P;B
Vest4		0.66
MutPred		0.40		Gain of catalytic residue at F136 (P = 0.0479);Gain of catalytic residue at F136 (P = 0.0479);Gain of catalytic residue at F136 (P = 0.0479);Gain of catalytic residue at F136 (P = 0.0479);Gain of catalytic residue at F136 (P = 0.0479);
MVP		0.42
MPC		0.88
ClinPred		0.85	D
GERP RS		4.9
Varity_R		0.066
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs193921109; hg19: chr20-9343581; COSMIC: COSV53797177;