NM_002660.3:c.787G>T

Variant names:

• chr20-41163273-G-T
• rs780081401
• NM_002660.3:c.787G>T

Variant summary

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

The NM_002660.3(PLCG1):​c.787G>T​(p.Gly263Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000212 in 1,416,410 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. 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. G263R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLCG1 NM_002660.3 missense, splice_region
• Scores: Splicing: ADA: 0.9827
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.90
• Publications: 0 publications found

Genes affected

PLCG1 (HGNC:9065): (phospholipase C gamma 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 receptor-mediated tyrosine kinase activators. For example, when activated by SRC, the encoded protein causes the Ras guanine nucleotide exchange factor RasGRP1 to translocate to the Golgi, where it activates Ras. Also, this protein has been shown to be a major substrate for heparin-binding growth factor 1 (acidic fibroblast growth factor)-activated tyrosine kinase. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PLCG1 Gene-Disease associations (from GenCC):

• immune dysregulation, autoimmunity, and autoinflammation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002660.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG1	NM_002660.3	MANE Select	c.787G>T	p.Gly263Trp	missense splice_region	Exon 8 of 32	NP_002651.2
	PLCG1	NM_182811.2		c.787G>T	p.Gly263Trp	missense splice_region	Exon 8 of 32	NP_877963.1	P19174-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCG1	ENST00000685551.1	MANE Select	c.787G>T	p.Gly263Trp	missense splice_region	Exon 8 of 32	ENSP00000508698.1	P19174-2
	PLCG1	ENST00000373271.5	TSL:1	c.787G>T	p.Gly263Trp	missense splice_region	Exon 8 of 32	ENSP00000362368.1	P19174-1
	PLCG1	ENST00000244007.7	TSL:5	c.787G>T	p.Gly263Trp	missense splice_region	Exon 9 of 33	ENSP00000244007.3	P19174-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1416410 Hom.: 0 Cov.: 31 AF XY: 0.00000285 AC XY: 2 AN XY: 700854

⚠️ 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: 31674

American (AMR) AF: 0.00 AC: 0 AN: 37356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22948

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090602

Other (OTH) AF: 0.00 AC: 0 AN: 58204

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	36
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.060	T
Polyphen		0.98	D
Vest4		0.50
MutPred		0.53		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.39
ClinPred		0.81	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.61
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.72
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.85		Position offset: -2

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

Other links and lift over

dbSNP: rs780081401; hg19: chr20-39791913;