Genetic Variant PLCH1:p.Pro1611Ser (chr3-155481195-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014996.4(PLCH1):c.4831C>T(p.Pro1611Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1611T) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PLCH1
NM_014996.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.83

Publications

0 publications found

Variant links:

Genes affected

PLCH1 (HGNC:29185): (phospholipase C eta 1) PLCH1 is a member of the PLC-eta family of the phosphoinositide-specific phospholipase C (PLC) superfamily of enzymes that cleave phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to generate second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (Hwang et al., 2005 [PubMed 15702972]).[supplied by OMIM, Jun 2009]

PLCH1 Gene-Disease associations (from GenCC):

holoprosencephaly 14
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

PLCH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08437091).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014996.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCH1	NM_014996.4	MANE Select	c.4831C>T	p.Pro1611Ser	missense	Exon 23 of 23	NP_055811.2	A0A2U3TZV8
PLCH1	NM_001130960.2		c.4855C>T	p.Pro1619Ser	missense	Exon 23 of 23	NP_001124432.1	Q4KWH8-1
PLCH1	NM_001349251.2		c.4828C>T	p.Pro1610Ser	missense	Exon 23 of 23	NP_001336180.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLCH1	ENST00000460012.7	TSL:5 MANE Select	c.4831C>T	p.Pro1611Ser	missense	Exon 23 of 23	ENSP00000417502.2	A0A2U3TZV8
PLCH1	ENST00000340059.11	TSL:1	c.4855C>T	p.Pro1619Ser	missense	Exon 23 of 23	ENSP00000345988.7	Q4KWH8-1
PLCH1	ENST00000334686.6	TSL:1	c.4741C>T	p.Pro1581Ser	missense	Exon 22 of 22	ENSP00000335469.6	Q4KWH8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.069

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.75

M_CAP

Benign

0.0051

MetaRNN

Benign

0.084

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

2.8

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.3

REVEL

Benign

0.054

Sift

Benign

0.13

Sift4G

Benign

0.47

Polyphen

0.0030

Vest4

0.043

MutPred

0.22

Gain of MoRF binding (P = 0.0359)

MVP

0.46

MPC

0.045

ClinPred

0.10

GERP RS

2.5

Varity_R

0.037

gMVP

0.29

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over