chr2-46612348-G-GA

Position:

• chr2-46612348-G-GA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_002643.4(PIGF):​c.321-5_321-4insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 782,374 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.056 (3 hom.)
• Consequence: PIGF NM_002643.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.210

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 Benign. Variant got -9 ACMG points.

• BP6: Variant 2-46612348-G-GA is Benign according to our data. Variant chr2-46612348-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 3352498.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGF	NM_002643.4	c.321-5_321-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000281382.11	NP_002634.1
PIGF	NM_173074.3	c.321-5_321-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_775097.1
PIGF	XM_005264369.4	c.321-5_321-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_005264426.1
PIGF	XM_011532908.4	c.321-5_321-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011531210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGF	ENST00000281382.11	c.321-5_321-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002643.4	ENSP00000281382	P1
PIGF	ENST00000306465.8	c.321-5_321-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000302663
PIGF	ENST00000412717.1	c.229-5_229-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		3		ENSP00000413202
PIGF	ENST00000495933.1	n.3338-5_3338-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000225 AC: 30 AN: 133302 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000222

Gnomad ASJ AF: 0.000315

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000236

Gnomad FIN AF: 0.00143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0590 AC: 3282 AN: 55674 Hom.: 0 AF XY: 0.0667 AC XY: 1967 AN XY: 29510

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.0797

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.0589

Gnomad SAS exome AF: 0.118

Gnomad FIN exome AF: 0.0191

Gnomad NFE exome AF: 0.0544

Gnomad OTH exome AF: 0.0761

GnomAD4 exome AF: 0.0559 AC: 36277 AN: 649020 Hom.: 3 Cov.: 10 AF XY: 0.0573 AC XY: 18956 AN XY: 330668

Gnomad4 AFR exome AF: 0.0496

Gnomad4 AMR exome AF: 0.0547

Gnomad4 ASJ exome AF: 0.0699

Gnomad4 EAS exome AF: 0.0659

Gnomad4 SAS exome AF: 0.0711

Gnomad4 FIN exome AF: 0.0427

Gnomad4 NFE exome AF: 0.0549

Gnomad4 OTH exome AF: 0.0595

GnomAD4 genome AF: 0.000232 AC: 31 AN: 133354 Hom.: 0 Cov.: 32 AF XY: 0.000233 AC XY: 15 AN XY: 64360

Gnomad4 AFR AF: 0.000138

Gnomad4 AMR AF: 0.000222

Gnomad4 ASJ AF: 0.000315

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000237

Gnomad4 FIN AF: 0.00143

Gnomad4 NFE AF: 0.000164

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PIGF-related condition Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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: rs747809849; hg19: chr2-46839487;