20-9307875-G-C

Position:

• chr20-9307875-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001377142.1(PLCB4):​c.61G>C​(p.Ala21Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PLCB4 NM_001377142.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.01

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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLCB4	NM_001377142.1	c.61G>C	p.Ala21Pro	missense_variant	4/40	ENST00000378473.9	NP_001364071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLCB4	ENST00000378473.9	c.61G>C	p.Ala21Pro	missense_variant	4/40	1	NM_001377142.1	ENSP00000367734

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;T;T;T;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;.;.;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.7	.;.;L;.;.;L;L;L;L
MutationTaster	Benign	0.0000085	P;P;P;P;P
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D;D;N;D;D;N;D;N;N
REVEL	Benign	0.25
Sift	Benign	0.043	D;T;T;T;T;T;D;T;T
Sift4G	Benign	0.066	T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.99	.;.;.;.;.;D;.;D;D
Vest4		0.76, 0.75, 0.77, 0.76
MutPred		0.45		Gain of disorder (P = 0.071);Gain of disorder (P = 0.071);Gain of disorder (P = 0.071);Gain of disorder (P = 0.071);Gain of disorder (P = 0.071);Gain of disorder (P = 0.071);Gain of disorder (P = 0.071);Gain of disorder (P = 0.071);Gain of disorder (P = 0.071);
MVP		0.64
MPC		1.8
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.57
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-9288522;