NM_001377142.1:c.448C>A

Variant names:

• chr20-9362974-C-A
• rs759189106
• NM_001377142.1:c.448C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001377142.1(PLCB4):​c.448C>A​(p.His150Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. H150Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLCB4 NM_001377142.1 missense, splice_region
• Scores: Splicing: ADA: 0.9651
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.35
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.448C>A	p.His150Asn	missense splice_region	Exon 8 of 40	NP_001364071.1
	PLCB4	NM_001377143.1		c.448C>A	p.His150Asn	missense splice_region	Exon 7 of 39	NP_001364072.1
	PLCB4	NM_000933.4		c.448C>A	p.His150Asn	missense splice_region	Exon 8 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.448C>A	p.His150Asn	missense splice_region	Exon 8 of 40	ENSP00000367734.5
	PLCB4	ENST00000278655.9	TSL:1	c.448C>A	p.His150Asn	missense splice_region	Exon 7 of 36	ENSP00000278655.5
	PLCB4	ENST00000685298.1		c.448C>A	p.His150Asn	missense splice_region	Exon 8 of 39	ENSP00000509390.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448514 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 721480

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

African (AFR) AF: 0.00 AC: 0 AN: 33250

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100114

Other (OTH) AF: 0.00 AC: 0 AN: 59940

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.23
Sift	Benign	0.13	T
Sift4G	Benign	0.32	T
Polyphen		0.98	D
Vest4		0.90
MutPred		0.49		Gain of MoRF binding (P = 0.1142)
MVP		0.78
MPC		1.8
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.58
gMVP		0.62
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.77
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

Other links and lift over

dbSNP: rs759189106; hg19: chr20-9343621;