chr20-41164170-A-C

Variant names:

• chr20-41164170-A-C
• rs779874773
• NM_002660.3:c.1186A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_002660.3(PLCG1):​c.1186A>C​(p.Thr396Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PLCG1 NM_002660.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.52

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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLCG1	NM_002660.3	c.1186A>C	p.Thr396Pro	missense_variant	Exon 12 of 32	ENST00000685551.1	NP_002651.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLCG1	ENST00000685551.1	c.1186A>C	p.Thr396Pro	missense_variant	Exon 12 of 32		NM_002660.3	ENSP00000508698.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 67 AN: 151740 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00176

Gnomad SAS AF: 0.00314

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000199 AC: 29 AN: 1458612 Hom.: 0 Cov.: 32 AF XY: 0.0000207 AC XY: 15 AN XY: 725654

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000435 AC: 66 AN: 151862 Hom.: 0 Cov.: 31 AF XY: 0.000431 AC XY: 32 AN XY: 74246

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00176

Gnomad4 SAS AF: 0.00314

Gnomad4 FIN AF: 0.000379

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.056	T;T
Polyphen		0.47	P;P
Vest4		0.79
MutPred		0.84		Gain of methylation at K398 (P = 0.11);Gain of methylation at K398 (P = 0.11);
MVP		0.90
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.80
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs779874773; hg19: chr20-39792810;