2-46614975-G-T

Position:

• chr2-46614975-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002643.4(PIGF):​c.190C>A​(p.Pro64Thr) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIGF NM_002643.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23508808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGF	NM_002643.4	c.190C>A	p.Pro64Thr	missense_variant	2/6	ENST00000281382.11	NP_002634.1
PIGF	NM_173074.3	c.190C>A	p.Pro64Thr	missense_variant	2/7		NP_775097.1
PIGF	XM_011532908.4	c.190C>A	p.Pro64Thr	missense_variant	2/7		XP_011531210.1
PIGF	XM_005264369.4	c.190C>A	p.Pro64Thr	missense_variant	2/6		XP_005264426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGF	ENST00000281382.11	c.190C>A	p.Pro64Thr	missense_variant	2/6	1	NM_002643.4	ENSP00000281382	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.190C>A (p.P64T) alteration is located in exon 2 (coding exon 1) of the PIGF gene. This alteration results from a C to A substitution at nucleotide position 190, causing the proline (P) at amino acid position 64 to be replaced by a threonine (T). 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	0.092
BayesDel_addAF	Benign	0.0041	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.072	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.24	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.34	B;D
Vest4		0.30
MutPred		0.54		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.45
MPC		0.0074
ClinPred		0.77	D
GERP RS		4.4
Varity_R		0.20
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1670561604; hg19: chr2-46842114;