20-9362974-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS1

The NM_001377142.1(PLCB4):c.448C>T(p.His150Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00003 in 1,600,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H150D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

PLCB4
NM_001377142.1 missense, splice_region

Scores

Splicing: ADA: 0.9924

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 7.35

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

auriculocondylar syndrome 2
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Illumina, Ambry Genetics
auriculocondylar syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PLCB4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 20-9362974-C-T is Benign according to our data. Variant chr20-9362974-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 207904.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000304 (44/1448514) while in subpopulation EAS AF = 0.000959 (38/39618). AF 95% confidence interval is 0.000718. There are 0 homozygotes in GnomAdExome4. There are 30 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377142.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCB4	NM_001377142.1	MANE Select	c.448C>T	p.His150Tyr	missense splice_region	Exon 8 of 40	NP_001364071.1
PLCB4	NM_001377143.1		c.448C>T	p.His150Tyr	missense splice_region	Exon 7 of 39	NP_001364072.1
PLCB4	NM_000933.4		c.448C>T	p.His150Tyr	missense splice_region	Exon 8 of 39	NP_000924.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PLCB4	ENST00000378473.9	TSL:1 MANE Select	c.448C>T	p.His150Tyr	missense splice_region	Exon 8 of 40	ENSP00000367734.5
PLCB4	ENST00000278655.9	TSL:1	c.448C>T	p.His150Tyr	missense splice_region	Exon 7 of 36	ENSP00000278655.5
PLCB4	ENST00000685298.1		c.448C>T	p.His150Tyr	missense splice_region	Exon 8 of 39	ENSP00000509390.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000120

AC:

AN:

250152

AF XY:

0.000163

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00142

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000304

AC:

AN:

1448514

Hom.:

Cov.:

AF XY:

0.0000416

AC XY:

AN XY:

721480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33250

American (AMR)

AF:

0.00

AC:

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.000959

AC:

AN:

39618

South Asian (SAS)

AF:

0.0000699

AC:

AN:

85780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100114

Other (OTH)

AF:

0.00

AC:

AN:

59940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000577

AC:

AN:

5198

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0352202), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000261

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Medical Research Institute, Tokyo Medical and Dental University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.027

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.7

PhyloP100

7.3

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.4

REVEL

Benign

0.26

Sift

Benign

0.13

Sift4G

Benign

0.29

Polyphen

0.98

Vest4

0.89

MutPred

0.43

Loss of catalytic residue at M152 (P = 0.1141)

MVP

0.74

MPC

1.8

ClinPred

0.18

GERP RS

5.9

Varity_R

0.40

gMVP

0.68

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.79

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over