2-46612348-G-GA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_002643.4(PIGF):​c.321-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0464 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, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Likely_benign. The variant received -5 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 VariationId is 3352498.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.321-5dupT		splice_region intron	N/A	NP_002634.1	Q6IB04
	PIGF	NM_173074.3		c.321-5dupT		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.321-5_321-4insT		splice_region intron	N/A	ENSP00000281382.6	Q07326-1
	PIGF	ENST00000306465.8	TSL:1	c.321-5_321-4insT		splice_region intron	N/A	ENSP00000302663.4	Q07326-2
	PIGF	ENST00000903157.1		c.321-5_321-4insT		splice_region intron	N/A	ENSP00000573216.1

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

GnomAD2 exomes AF: 0.0590 AC: 3282 AN: 55674 AF XY: 0.0667

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 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

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

African (AFR) AF: 0.0496 AC: 716 AN: 14442

American (AMR) AF: 0.0547 AC: 798 AN: 14584

Ashkenazi Jewish (ASJ) AF: 0.0699 AC: 855 AN: 12236

East Asian (EAS) AF: 0.0659 AC: 1294 AN: 19638

South Asian (SAS) AF: 0.0711 AC: 2766 AN: 38888

European-Finnish (FIN) AF: 0.0427 AC: 1371 AN: 32088

Middle Eastern (MID) AF: 0.0361 AC: 124 AN: 3436

European-Non Finnish (NFE) AF: 0.0549 AC: 26723 AN: 486320

Other (OTH) AF: 0.0595 AC: 1630 AN: 27388

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

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

African (AFR) AF: 0.000138 AC: 5 AN: 36362

American (AMR) AF: 0.000222 AC: 3 AN: 13534

Ashkenazi Jewish (ASJ) AF: 0.000315 AC: 1 AN: 3170

East Asian (EAS) AF: 0.00 AC: 0 AN: 4600

South Asian (SAS) AF: 0.000237 AC: 1 AN: 4220

European-Finnish (FIN) AF: 0.00143 AC: 11 AN: 7700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.000164 AC: 10 AN: 60858

Other (OTH) AF: 0.00 AC: 0 AN: 1816

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PIGF-related condition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism

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;