NM_014996.4:c.4882G>C

Variant names:

• chr3-155481144-C-G
• rs142695210
• NM_014996.4:c.4882G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014996.4(PLCH1):​c.4882G>C​(p.Ala1628Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A1628S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLCH1 NM_014996.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.33
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCH1	NM_014996.4	MANE Select	c.4882G>C	p.Ala1628Pro	missense	Exon 23 of 23	NP_055811.2	A0A2U3TZV8
	PLCH1	NM_001130960.2		c.4906G>C	p.Ala1636Pro	missense	Exon 23 of 23	NP_001124432.1	Q4KWH8-1
	PLCH1	NM_001349251.2		c.4879G>C	p.Ala1627Pro	missense	Exon 23 of 23	NP_001336180.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLCH1	ENST00000460012.7	TSL:5 MANE Select	c.4882G>C	p.Ala1628Pro	missense	Exon 23 of 23	ENSP00000417502.2	A0A2U3TZV8
	PLCH1	ENST00000340059.11	TSL:1	c.4906G>C	p.Ala1636Pro	missense	Exon 23 of 23	ENSP00000345988.7	Q4KWH8-1
	PLCH1	ENST00000334686.6	TSL:1	c.4792G>C	p.Ala1598Pro	missense	Exon 22 of 22	ENSP00000335469.6	Q4KWH8-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.48		Gain of glycosylation at Y1634 (P = 0.0082)
MVP		0.81
MPC		0.34
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.33
gMVP		0.76
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs142695210; hg19: chr3-155198933;