20-9387476-G-A

Variant names:

• chr20-9387476-G-A
• rs397514770
• NM_001377142.1:c.1078G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001377142.1(PLCB4):​c.1078G>A​(p.Asp360Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D360V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLCB4 NM_001377142.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.98
• Publications: 4 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-9387477-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 64695.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 20-9387476-G-A is Pathogenic according to our data. Variant chr20-9387476-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 64694.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB4	NM_001377142.1	MANE Select	c.1078G>A	p.Asp360Asn	missense	Exon 15 of 40	NP_001364071.1
	PLCB4	NM_001377143.1		c.1078G>A	p.Asp360Asn	missense	Exon 14 of 39	NP_001364072.1
	PLCB4	NM_000933.4		c.1078G>A	p.Asp360Asn	missense	Exon 15 of 39	NP_000924.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCB4	ENST00000378473.9	TSL:1 MANE Select	c.1078G>A	p.Asp360Asn	missense	Exon 15 of 40	ENSP00000367734.5
	PLCB4	ENST00000278655.9	TSL:1	c.1024G>A	p.Asp342Asn	missense	Exon 13 of 36	ENSP00000278655.5
	PLCB4	ENST00000464199.5	TSL:1	n.855G>A		non_coding_transcript_exon	Exon 6 of 29

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Auriculocondylar syndrome 2 Pathogenic:1

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.84		Gain of methylation at R355 (P = 0.188)
MVP		0.91
MPC		1.7
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.93
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397514770; hg19: chr20-9368123;