Genetic Variant PLCG1:p.Leu25Phe (chr20-41137714-C-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4BS2

The NM_002660.3(PLCG1):c.73C>T(p.Leu25Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000431 in 1,160,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

PLCG1
NM_002660.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.92

Publications

0 publications found

Variant links:

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 links:

PLCG1-AS1 (HGNC:40450): (PLCG1 antisense RNA 1)

PLCG1-AS1 links:

LOC124904903 (HGNC:):

LOC124904903 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34183612).

BS2

High AC in GnomAdExome4 at 5 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCG1	NM_002660.3	MANE Select	c.73C>T	p.Leu25Phe	missense	Exon 1 of 32	NP_002651.2
PLCG1	NM_182811.2		c.73C>T	p.Leu25Phe	missense	Exon 1 of 32	NP_877963.1	P19174-1
PLCG1-AS1	NR_109889.1		n.287G>A		splice_region non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCG1	ENST00000685551.1	MANE Select	c.73C>T	p.Leu25Phe	missense	Exon 1 of 32	ENSP00000508698.1	P19174-2
PLCG1	ENST00000373271.5	TSL:1	c.73C>T	p.Leu25Phe	missense	Exon 1 of 32	ENSP00000362368.1	P19174-1
PLCG1-AS1	ENST00000454626.1	TSL:1	n.290G>A		splice_region non_coding_transcript_exon	Exon 1 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000431

AC:

AN:

1160648

Hom.:

Cov.:

AF XY:

0.00000359

AC XY:

AN XY:

557264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23408

American (AMR)

AF:

0.00

AC:

AN:

9390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15458

East Asian (EAS)

AF:

0.00

AC:

AN:

27022

South Asian (SAS)

AF:

0.00

AC:

AN:

36420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4660

European-Non Finnish (NFE)

AF:

0.00000522

AC:

AN:

957948

Other (OTH)

AF:

0.00

AC:

AN:

46640

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.60

MutationAssessor

Benign

2.0

PhyloP100

3.9

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-2.0

REVEL

Benign

0.13

Sift

Uncertain

0.016

Sift4G

Uncertain

0.019

Polyphen

0.85

Vest4

0.30

MutPred

0.38

Loss of helix (P = 0.028)

MVP

0.54

ClinPred

0.95

GERP RS

3.4

PromoterAI

0.029

Neutral

(source)

Varity_R

0.44

gMVP

0.45

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over