rs6077510

chr20-9307875-G-Achr20-9307875-G-Cchr20-9307875-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001377142.1(PLCB4):c.61G>A(p.Ala21Thr) variant causes a missense change. The variant allele was found at a frequency of 0.633 in 1,557,610 control chromosomes in the GnomAD database, including 323,537 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.52 (23573 hom., cov: 31)
  • Exomes 𝑓: 0.65 (299964 hom.)
• Consequence: PLCB4 NM_001377142.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PLCB4
• BP4: Computational evidence support a benign effect (MetaRNN=1.0471891E-5).
• BP6: Variant 20-9307875-G-A is Benign according to our data. Variant chr20-9307875-G-A is described in ClinVar as [Benign]. Clinvar id is 339552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-9307875-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLCB4	NM_001377142.1	c.61G>A	p.Ala21Thr	missense_variant	4/40	ENST00000378473.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLCB4	ENST00000378473.9	c.61G>A	p.Ala21Thr	missense_variant	4/40	1	NM_001377142.1

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78385 AN: 151814 Hom.: 23566 Cov.: 31

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.673

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.565

GnomAD3 exomes AF: 0.596 AC: 147393 AN: 247122 Hom.: 46298 AF XY: 0.610 AC XY: 81429 AN XY: 133598

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.591

Gnomad ASJ exome AF: 0.713

Gnomad EAS exome AF: 0.429

Gnomad SAS exome AF: 0.626

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.677

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.646 AC: 907575 AN: 1405678 Hom.: 299964 Cov.: 23 AF XY: 0.648 AC XY: 454891 AN XY: 702170

Gnomad4 AFR exome AF: 0.175

Gnomad4 AMR exome AF: 0.589

Gnomad4 ASJ exome AF: 0.704

Gnomad4 EAS exome AF: 0.442

Gnomad4 SAS exome AF: 0.623

Gnomad4 FIN exome AF: 0.534

Gnomad4 NFE exome AF: 0.677

Gnomad4 OTH exome AF: 0.631

GnomAD4 genome AF: 0.516 AC: 78393 AN: 151932 Hom.: 23573 Cov.: 31 AF XY: 0.512 AC XY: 38046 AN XY: 74250

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.577

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.622

Gnomad4 FIN AF: 0.534

Gnomad4 NFE AF: 0.679

Gnomad4 OTH AF: 0.570

Alfa AF: 0.652 Hom.: 61597

Bravo AF: 0.505

TwinsUK AF: 0.685 AC: 2539

ALSPAC AF: 0.680 AC: 2621

ESP6500AA AF: 0.211 AC: 930

ESP6500EA AF: 0.673 AC: 5785

ExAC AF: 0.593 AC: 72006

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Auriculocondylar syndrome 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Benign	0.96
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;.;.;D
MetaRNN	Benign	0.000010	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.000028	P;P;P;P;P
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.35	T;T;T;T;T;T;D;T;T
Sift4G	Benign	0.44	T;T;T;T;D;T;T;T;T
Polyphen		0.99, 0.93	.;.;.;.;.;D;.;D;P
Vest4		0.30, 0.26, 0.23, 0.39, 0.27
MPC		0.69
ClinPred		0.018	T
GERP RS		5.9
Varity_R		0.20
gMVP		0.24

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: rs6077510; hg19: chr20-9288522; COSMIC: COSV53802870;