2-46592543-T-C

Position:

• chr2-46592543-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002643.4(PIGF):​c.478A>G​(p.Ile160Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,456,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PIGF NM_002643.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0620

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044166774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGF	NM_002643.4	c.478A>G	p.Ile160Val	missense_variant	5/6	ENST00000281382.11	NP_002634.1
PIGF	NM_173074.3	c.478A>G	p.Ile160Val	missense_variant	5/7		NP_775097.1
PIGF	XM_011532908.4	c.478A>G	p.Ile160Val	missense_variant	5/7		XP_011531210.1
PIGF	XM_005264369.4	c.478A>G	p.Ile160Val	missense_variant	5/6		XP_005264426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGF	ENST00000281382.11	c.478A>G	p.Ile160Val	missense_variant	5/6	1	NM_002643.4	ENSP00000281382	P1
PIGF	ENST00000306465.8	c.478A>G	p.Ile160Val	missense_variant	5/7	1		ENSP00000302663
PIGF	ENST00000420164.5	c.88A>G	p.Ile30Val	missense_variant, NMD_transcript_variant	2/4	5		ENSP00000410361
PIGF	ENST00000412717.1	c.*47A>G		3_prime_UTR_variant, NMD_transcript_variant	4/5	3		ENSP00000413202

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1456624 Hom.: 0 Cov.: 27 AF XY: 0.00000276 AC XY: 2 AN XY: 725024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Apr 11, 2023

The c.478A>G (p.I160V) alteration is located in exon 5 (coding exon 4) of the PIGF gene. This alteration results from a A to G substitution at nucleotide position 478, causing the isoleucine (I) at amino acid position 160 to be replaced by a valine (V). 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	0.061
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.2
DANN	Benign	0.64
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.00090	T
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N;N
MutationTaster	Benign	0.94	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.027
Sift	Benign	0.87	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0	B;B
Vest4		0.10
MutPred		0.38		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.29
MPC		0.0065
ClinPred		0.073	T
GERP RS		-0.47
Varity_R		0.041
gMVP		0.20

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

LitVar

Other links and lift over

dbSNP: rs1434404549; hg19: chr2-46819682;