20-41162529-G-T

Variant names:

• chr20-41162529-G-T
• NM_002660.3:c.590G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002660.3(PLCG1):​c.590G>T​(p.Arg197Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PLCG1 NM_002660.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG1	NM_002660.3	c.590G>T	p.Arg197Leu	missense_variant	Exon 5 of 32	ENST00000685551.1	NP_002651.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG1	ENST00000685551.1	c.590G>T	p.Arg197Leu	missense_variant	Exon 5 of 32		NM_002660.3	ENSP00000508698.1
PLCG1	ENST00000373271.5	c.590G>T	p.Arg197Leu	missense_variant	Exon 5 of 32	1		ENSP00000362368.1
PLCG1	ENST00000244007.7	c.590G>T	p.Arg197Leu	missense_variant	Exon 6 of 33	5		ENSP00000244007.3
PLCG1	ENST00000483646.2	n.578G>T		non_coding_transcript_exon_variant	Exon 5 of 6	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immune dysregulation, autoimmunity, and autoinflammation Uncertain:1

Dec 02, 2024

Paediatric Laboratory, Institute for Maternal and Child Health - IRCCS Burlo Garofolo

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_002660.3:c.590G>T variant is predicted to result in the substitution of the arginine residue at position 197 with a leucine. This variant is absent from the gnomAD v4.1.0 population database [PM2] and occurs in a gene with low tolerance for benign missense variation, as indicated by a Z-score > 3 for missense variants [PP2]. However, multiple lines of computational evidence suggest little to no impact on the gene or its product [BP4]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0069	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.38	N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.20
Sift	Benign	0.68	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.0020	.;B
Vest4		0.68
MutPred		0.56		Loss of MoRF binding (P = 0.0373);Loss of MoRF binding (P = 0.0373);
MVP		0.56
ClinPred		0.83	D
GERP RS		5.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1
Varity_R		0.19
gMVP		0.50

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-39791169; COSMIC: COSV54817523; COSMIC: COSV54817523;