20-9307875-G-A

Position:

chr20-9307875-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000378473.9(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
ENST00000378473.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.01

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]

PLCB4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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=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	Protein	UniProt
PLCB4	NM_001377142.1 linkuse as main transcript	c.61G>A	p.Ala21Thr	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 linkuse as main transcript	c.61G>A	p.Ala21Thr	missense_variant	4/40	1	NM_001377142.1	ENSP00000367734

Frequencies

GnomAD3 genomes

AF:

0.516

AC:

78385

AN:

151814

Hom.:

23566

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.648

AC XY:

454891

AN XY:

702170

show subpopulations

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.:

AF XY:

0.512

AC XY:

38046

AN XY:

74250

show subpopulations

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.32

.;T;.;T;T;T;.;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

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

MutationAssessor

Benign

1.4

.;.;L;.;.;L;L;L;L

MutationTaster

Benign

0.000028

P;P;P;P;P

PrimateAI

Uncertain

0.63

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over