rs759189106

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr20-9362974-C-A
• chr20-9362974-C-G
• chr20-9362974-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 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.

• 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

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the PLCB4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 3.5718 (above the threshold of 3.09). Trascript score misZ: 3.2758 (above the threshold of 3.09). GenCC associations: The gene is linked to auriculocondylar syndrome 1, auriculocondylar syndrome, auriculocondylar syndrome 2.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB4	NM_001377142.1	c.448C>A	p.His150Asn	missense_variant, splice_region_variant	Exon 8 of 40	ENST00000378473.9	NP_001364071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCB4	ENST00000378473.9	c.448C>A	p.His150Asn	missense_variant, splice_region_variant	Exon 8 of 40	1	NM_001377142.1	ENSP00000367734.5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;.;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;.;.;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.6	L;L;L;L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D;D;.;D;D
REVEL	Benign	0.23
Sift	Benign	0.13	T;T;.;T;T
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.98, 0.85	.;D;.;D;P
Vest4		0.90
MutPred		0.49		Gain of MoRF binding (P = 0.1142);Gain of MoRF binding (P = 0.1142);Gain of MoRF binding (P = 0.1142);Gain of MoRF binding (P = 0.1142);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-9343621;