NM_014996.4:c.4831C>A

Variant names:

• chr3-155481195-G-T
• rs148331765
• NM_014996.4:c.4831C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014996.4(PLCH1):​c.4831C>A​(p.Pro1611Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 1,614,224 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0044 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (4 hom.)
• Consequence: PLCH1 NM_014996.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.83
• Publications: 2 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049954355).
• BP6: Variant 3-155481195-G-T is Benign according to our data. Variant chr3-155481195-G-T is described in ClinVar as Benign. ClinVar VariationId is 774851.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.4831C>A	p.Pro1611Thr	missense	Exon 23 of 23	NP_055811.2	A0A2U3TZV8
	PLCH1	NM_001130960.2		c.4855C>A	p.Pro1619Thr	missense	Exon 23 of 23	NP_001124432.1	Q4KWH8-1
	PLCH1	NM_001349251.2		c.4828C>A	p.Pro1610Thr	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.4831C>A	p.Pro1611Thr	missense	Exon 23 of 23	ENSP00000417502.2	A0A2U3TZV8
	PLCH1	ENST00000340059.11	TSL:1	c.4855C>A	p.Pro1619Thr	missense	Exon 23 of 23	ENSP00000345988.7	Q4KWH8-1
	PLCH1	ENST00000334686.6	TSL:1	c.4741C>A	p.Pro1581Thr	missense	Exon 22 of 22	ENSP00000335469.6	Q4KWH8-2

Frequencies

GnomAD3 genomes AF: 0.00441 AC: 672 AN: 152214 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00120 AC: 301 AN: 251490 AF XY: 0.000773

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000612 AC: 895 AN: 1461892 Hom.: 4 Cov.: 33 AF XY: 0.000492 AC XY: 358 AN XY: 727246

African (AFR) AF: 0.0158 AC: 530 AN: 33480

American (AMR) AF: 0.00107 AC: 48 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

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: 0.000214 AC: 238 AN: 1112012

Other (OTH) AF: 0.00124 AC: 75 AN: 60396

GnomAD4 genome AF: 0.00442 AC: 673 AN: 152332 Hom.: 6 Cov.: 33 AF XY: 0.00393 AC XY: 293 AN XY: 74478

African (AFR) AF: 0.0153 AC: 637 AN: 41582

American (AMR) AF: 0.00111 AC: 17 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68040

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00189 Hom.: 2

Bravo AF: 0.00505

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00149 AC: 181

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.055
Sift	Uncertain	0.012	D
Sift4G	Benign	0.31	T
Polyphen		0.22	B
Vest4		0.14
MVP		0.48
MPC		0.083
ClinPred		0.037	T
GERP RS		2.5
Varity_R		0.069
gMVP		0.31
Mutation Taster		=100/0	polymorphism

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: rs148331765; hg19: chr3-155198984;