chr20-41160141-A-G

Variant names:

• chr20-41160141-A-G
• rs907973449
• NM_002660.3:c.500A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_002660.3(PLCG1):​c.500A>G​(p.Asn167Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: PLCG1 NM_002660.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.57

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity PLCG1_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.23926133).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG1	NM_002660.3	c.500A>G	p.Asn167Ser	missense_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.500A>G	p.Asn167Ser	missense_variant	Exon 4 of 32		NM_002660.3	ENSP00000508698.1
PLCG1	ENST00000373271.5	c.500A>G	p.Asn167Ser	missense_variant	Exon 4 of 32	1		ENSP00000362368.1
PLCG1	ENST00000244007.7	c.500A>G	p.Asn167Ser	missense_variant	Exon 5 of 33	5		ENSP00000244007.3
PLCG1	ENST00000483646.2	n.410A>G		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461772 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727194

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500A>G (p.N167S) alteration is located in exon 4 (coding exon 4) of the PLCG1 gene. This alteration results from a A to G substitution at nucleotide position 500, causing the asparagine (N) at amino acid position 167 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.87	N;N
REVEL	Benign	0.045
Sift	Benign	0.49	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0	.;B
Vest4		0.41
MutPred		0.33		Gain of phosphorylation at N167 (P = 0.0117);Gain of phosphorylation at N167 (P = 0.0117);
MVP		0.48
ClinPred		0.59	D
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.096
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs907973449; hg19: chr20-39788781;