20-41160152-C-T

Variant names:

• chr20-41160152-C-T
• rs866700700
• NM_002660.3:c.511C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002660.3(PLCG1):​c.511C>T​(p.Arg171Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLCG1 NM_002660.3 missense, splice_region
• Scores: Splicing: ADA: 0.9652
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.03

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 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity PLCG1_HUMAN
• 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.511C>T	p.Arg171Cys	missense_variant, splice_region_variant	Exon 4 of 32	ENST00000685551.1	NP_002651.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG1	ENST00000685551.1	c.511C>T	p.Arg171Cys	missense_variant, splice_region_variant	Exon 4 of 32		NM_002660.3	ENSP00000508698.1
PLCG1	ENST00000373271.5	c.511C>T	p.Arg171Cys	missense_variant, splice_region_variant	Exon 4 of 32	1		ENSP00000362368.1
PLCG1	ENST00000244007.7	c.511C>T	p.Arg171Cys	missense_variant, splice_region_variant	Exon 5 of 33	5		ENSP00000244007.3
PLCG1	ENST00000483646.2	n.421C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461538 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727130

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000306 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

PLCG1-related disorder Uncertain:1

Sep 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PLCG1 c.511C>T variant is predicted to result in the amino acid substitution p.Arg171Cys. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.76	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.011	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.79	.;P
Vest4		0.56
MutPred		0.45		Loss of MoRF binding (P = 0.0027);Loss of MoRF binding (P = 0.0027);
MVP		0.63
ClinPred		0.79	D
GERP RS		4.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.7
Varity_R		0.10
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.69
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

LitVar

Other links and lift over

dbSNP: rs866700700; hg19: chr20-39788792; COSMIC: COSV54825385; COSMIC: COSV54825385;