Genetic Variant NM_002643.4:c.321-6_321-5delTT (chr2-46612348-GAA-G) – ACMG Classification: Uncertain_significance (0 pts)

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.210

Publications

0 publications found

Variant links:

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)

PIGF links:

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ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PIGF	NM_002643.4 link	c.321-6_321-5delTT	splice_region_variant, intron_variant	Intron 3 of 5	ENST00000281382.11	NP_002634.1	Q07326-1Q6IB04
PIGF	NM_173074.3 link	c.321-6_321-5delTT	splice_region_variant, intron_variant	Intron 3 of 6		NP_775097.1	Q07326-2
PIGF	XM_011532908.4 link	c.321-6_321-5delTT	splice_region_variant, intron_variant	Intron 3 of 6		XP_011531210.1
PIGF	XM_005264369.4 link	c.321-6_321-5delTT	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 link	c.321-6_321-5delTT		splice_region_variant, intron_variant	Intron 3 of 5	1	NM_002643.4	ENSP00000281382.6		Q07326-1

Frequencies

GnomAD3 genomes

AF:

0.0000150

AC:

AN:

133358

Hom.:

Cov.:

show subpopulations

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:

AN:

55674

AF XY:

0.000576

show subpopulations

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.:

AF XY:

0.000179

AC XY:

AN XY:

357662

show subpopulations

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

African (AFR)

AF:

0.000129

AC:

AN:

15564

American (AMR)

AF:

0.000380

AC:

AN:

15798

Ashkenazi Jewish (ASJ)

AF:

0.0000733

AC:

AN:

13638

East Asian (EAS)

AF:

0.0000431

AC:

AN:

23224

South Asian (SAS)

AF:

0.000478

AC:

AN:

41824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3632

European-Non Finnish (NFE)

AF:

0.000137

AC:

AN:

518976

Other (OTH)

AF:

0.000200

AC:

AN:

30032

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.229

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000150

AC:

AN:

133358

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

36282

American (AMR)

AF:

0.00

AC:

AN:

13526

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3172

East Asian (EAS)

AF:

0.00

AC:

AN:

4612

South Asian (SAS)

AF:

0.00

AC:

AN:

4238

European-Finnish (FIN)

AF:

0.000130

AC:

AN:

7714

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0000164

AC:

AN:

60888

Other (OTH)

AF:

0.00

AC:

AN:

1810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

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NM_002643.4:c.321-6_321-5delTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over