chr20-9362934-C-A

Position:

• chr20-9362934-C-A

Variant summary

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

The NM_001377142.1(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 NM_001377142.1 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). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. GenCC has associacion of the 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	ENSP00000367734.5

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
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;