rs548635433

Variant names:

• chr20-8132484-G-A
• rs548635433
• NM_015192.4:c.-168G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_015192.4(PLCB1):​c.-168G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 364,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: PLCB1 NM_015192.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.282
• Publications: 0 publications found

Genes affected

PLCB1 (HGNC:15917): (phospholipase C beta 1) 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. This gene is activated by two G-protein alpha subunits, alpha-q and alpha-11. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PLCB1 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 12

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00106 (161/151910) while in subpopulation NFE AF = 0.00187 (127/67874). AF 95% confidence interval is 0.00161. There are 0 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCB1	NM_015192.4	c.-168G>A		5_prime_UTR_variant	Exon 1 of 32	ENST00000338037.11	NP_056007.1
PLCB1	NM_182734.3	c.-168G>A		5_prime_UTR_variant	Exon 1 of 33		NP_877398.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCB1	ENST00000338037.11	c.-168G>A		5_prime_UTR_variant	Exon 1 of 32	1	NM_015192.4	ENSP00000338185.6

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 162 AN: 151802 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00189

Gnomad OTH AF: 0.00288

GnomAD4 exome AF: 0.00168 AC: 357 AN: 212174 Hom.: 0 Cov.: 3 AF XY: 0.00172 AC XY: 188 AN XY: 109462

African (AFR) AF: 0.00 AC: 0 AN: 5190

American (AMR) AF: 0.00178 AC: 10 AN: 5612

Ashkenazi Jewish (ASJ) AF: 0.000145 AC: 1 AN: 6880

East Asian (EAS) AF: 0.00 AC: 0 AN: 17782

South Asian (SAS) AF: 0.00 AC: 0 AN: 3660

European-Finnish (FIN) AF: 0.000133 AC: 3 AN: 22498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1034

European-Non Finnish (NFE) AF: 0.00225 AC: 307 AN: 136642

Other (OTH) AF: 0.00280 AC: 36 AN: 12876

GnomAD4 genome AF: 0.00106 AC: 161 AN: 151910 Hom.: 0 Cov.: 32 AF XY: 0.000902 AC XY: 67 AN XY: 74258

African (AFR) AF: 0.000169 AC: 7 AN: 41482

American (AMR) AF: 0.00138 AC: 21 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 67874

Other (OTH) AF: 0.00285 AC: 6 AN: 2104

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.00131

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 12 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.95
PhyloP100		0.28
PromoterAI		-0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=298/2	polymorphism

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

Other links and lift over

dbSNP: rs548635433; hg19: chr20-8113131;