rs1222650814

Variant names:

• chr2-46613771-C-G
• rs1222650814
• NM_002643.4:c.243G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-46613771-C-G
• chr2-46613771-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002643.4(PIGF):​c.243G>C​(p.Leu81Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIGF NM_002643.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• Publications: 0 publications found

Genes affected

PIGF (HGNC:8962): (phosphatidylinositol glycan anchor biosynthesis class F) This gene encodes a protein involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor, a glycolipid containing three mannose molecules in its core backbone, is found on many blood cells where it serves to anchor proteins to the cell surface. The encoded protein and another GPI synthesis protein, PIGO, function in the transfer of ethanolaminephosphate to the third mannose in GPI. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

PIGF Gene-Disease associations (from GenCC):

• onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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=0.21460277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGF	NM_002643.4	c.243G>C	p.Leu81Phe	missense_variant	Exon 3 of 6	ENST00000281382.11	NP_002634.1
PIGF	NM_173074.3	c.243G>C	p.Leu81Phe	missense_variant	Exon 3 of 7		NP_775097.1
PIGF	XM_011532908.4	c.243G>C	p.Leu81Phe	missense_variant	Exon 3 of 7		XP_011531210.1
PIGF	XM_005264369.4	c.243G>C	p.Leu81Phe	missense_variant	Exon 3 of 6		XP_005264426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGF	ENST00000281382.11	c.243G>C	p.Leu81Phe	missense_variant	Exon 3 of 6	1	NM_002643.4	ENSP00000281382.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 226064 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000285 AC: 4 AN: 1404438 Hom.: 0 Cov.: 24 AF XY: 0.00000143 AC XY: 1 AN XY: 700036

African (AFR) AF: 0.00 AC: 0 AN: 32042

American (AMR) AF: 0.00 AC: 0 AN: 41446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25372

East Asian (EAS) AF: 0.00 AC: 0 AN: 39122

South Asian (SAS) AF: 0.00 AC: 0 AN: 82146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00000375 AC: 4 AN: 1067482

Other (OTH) AF: 0.00 AC: 0 AN: 58408

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.243G>C (p.L81F) alteration is located in exon 3 (coding exon 2) of the PIGF gene. This alteration results from a G to C substitution at nucleotide position 243, causing the leucine (L) at amino acid position 81 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L;L
PhyloP100		1.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.063
Sift	Benign	0.12	T;D
Sift4G	Benign	0.21	T;T
Polyphen		0.0020	B;P
Vest4		0.34
MutPred		0.71		Gain of ubiquitination at K82 (P = 0.0872);Gain of ubiquitination at K82 (P = 0.0872);
MVP		0.18
MPC		0.0061
ClinPred		0.25	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.50
Mutation Taster		=83/17	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: rs1222650814; hg19: chr2-46840910;