2-46612348-GAAA-GAA

Variant names:

• chr2-46612348-GA-G
• rs747809849
• NM_002643.4:c.321-5delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_002643.4(PIGF):​c.321-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 805,170 control chromosomes in the GnomAD database, including 180 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.027 (143 hom., cov: 32)
  • Exomes 𝑓: 0.020 (37 hom.)
• Consequence: PIGF NM_002643.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210
• 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGF	NM_002643.4	c.321-5delT		splice_region_variant, intron_variant	Intron 3 of 5	ENST00000281382.11	NP_002634.1
PIGF	NM_173074.3	c.321-5delT		splice_region_variant, intron_variant	Intron 3 of 6		NP_775097.1
PIGF	XM_011532908.4	c.321-5delT		splice_region_variant, intron_variant	Intron 3 of 6		XP_011531210.1
PIGF	XM_005264369.4	c.321-5delT		splice_region_variant, intron_variant	Intron 3 of 5		XP_005264426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGF	ENST00000281382.11	c.321-5delT		splice_region_variant, intron_variant	Intron 3 of 5	1	NM_002643.4	ENSP00000281382.6

Frequencies

GnomAD3 genomes AF: 0.0267 AC: 3555 AN: 133294 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.0929

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00814

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000434

Gnomad SAS AF: 0.000708

Gnomad FIN AF: 0.000780

Gnomad MID AF: 0.00365

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.0205

GnomAD2 exomes AF: 0.0522 AC: 2906 AN: 55674 AF XY: 0.0516

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.0561

Gnomad ASJ exome AF: 0.0570

Gnomad EAS exome AF: 0.0493

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0453

Gnomad OTH exome AF: 0.0607

GnomAD4 exome AF: 0.0204 AC: 13713 AN: 671824 Hom.: 37 Cov.: 10 AF XY: 0.0208 AC XY: 7135 AN XY: 342844

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.104 AC: 1546 AN: 14920

American (AMR) AF: 0.0281 AC: 422 AN: 15006

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 267 AN: 12934

East Asian (EAS) AF: 0.0183 AC: 394 AN: 21512

South Asian (SAS) AF: 0.0313 AC: 1247 AN: 39868

European-Finnish (FIN) AF: 0.0133 AC: 466 AN: 35058

Middle Eastern (MID) AF: 0.0113 AC: 40 AN: 3538

European-Non Finnish (NFE) AF: 0.0172 AC: 8610 AN: 500348

Other (OTH) AF: 0.0252 AC: 721 AN: 28640

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0267 AC: 3557 AN: 133346 Hom.: 143 Cov.: 32 AF XY: 0.0261 AC XY: 1681 AN XY: 64360

African (AFR) AF: 0.0928 AC: 3373 AN: 36356

American (AMR) AF: 0.00813 AC: 110 AN: 13536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3172

East Asian (EAS) AF: 0.000435 AC: 2 AN: 4602

South Asian (SAS) AF: 0.000711 AC: 3 AN: 4222

European-Finnish (FIN) AF: 0.000780 AC: 6 AN: 7696

Middle Eastern (MID) AF: 0.00397 AC: 1 AN: 252

European-Non Finnish (NFE) AF: 0.000411 AC: 25 AN: 60852

Other (OTH) AF: 0.0204 AC: 37 AN: 1818

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0265

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=99/1	polymorphism (auto)

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: rs747809849; hg19: chr2-46839487;