chr2-46612348-GAA-G

Variant names:

• chr2-46612348-GAA-G
• rs747809849
• NM_002643.4:c.321-6_321-5delTT

Variant summary

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

The NM_002643.4(PIGF):​c.321-6_321-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 832,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 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), ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002643.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGF	NM_002643.4	MANE Select	c.321-6_321-5delTT		splice_region intron	N/A	NP_002634.1	Q6IB04
	PIGF	NM_173074.3		c.321-6_321-5delTT		splice_region intron	N/A	NP_775097.1	Q07326-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGF	ENST00000281382.11	TSL:1 MANE Select	c.321-6_321-5delTT		splice_region intron	N/A	ENSP00000281382.6	Q07326-1
	PIGF	ENST00000306465.8	TSL:1	c.321-6_321-5delTT		splice_region intron	N/A	ENSP00000302663.4	Q07326-2
	PIGF	ENST00000903157.1		c.321-6_321-5delTT		splice_region intron	N/A	ENSP00000573216.1

Frequencies

GnomAD3 genomes AF: 0.0000150 AC: 2 AN: 133358 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000164

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000521 AC: 29 AN: 55674 AF XY: 0.000576

Gnomad AFR exome AF: 0.000457

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000545

Gnomad FIN exome AF: 0.000134

Gnomad NFE exome AF: 0.000558

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 107 AN: 699276 Hom.: 0 AF XY: 0.000179 AC XY: 64 AN XY: 357662

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

African (AFR) AF: 0.000129 AC: 2 AN: 15564

American (AMR) AF: 0.000380 AC: 6 AN: 15798

Ashkenazi Jewish (ASJ) AF: 0.0000733 AC: 1 AN: 13638

East Asian (EAS) AF: 0.0000431 AC: 1 AN: 23224

South Asian (SAS) AF: 0.000478 AC: 20 AN: 41824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3632

European-Non Finnish (NFE) AF: 0.000137 AC: 71 AN: 518976

Other (OTH) AF: 0.000200 AC: 6 AN: 30032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000150 AC: 2 AN: 133358 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 64332

African (AFR) AF: 0.00 AC: 0 AN: 36282

American (AMR) AF: 0.00 AC: 0 AN: 13526

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4612

South Asian (SAS) AF: 0.00 AC: 0 AN: 4238

European-Finnish (FIN) AF: 0.000130 AC: 1 AN: 7714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000164 AC: 1 AN: 60888

Other (OTH) AF: 0.00 AC: 0 AN: 1810

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21

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

Other links and lift over

dbSNP: rs747809849; hg19: chr2-46839487;