dbSNP rs149499692: PIGF:p.His75Leu (chr2-46614941-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002643.4(PIGF):c.224A>T(p.His75Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000797 in 1,254,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H75R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.0e-7 ( 0 hom. )

Consequence

PIGF
NM_002643.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.90

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), ClinGen

PIGF links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30759943).

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.224A>T	p.His75Leu	missense	Exon 2 of 6	NP_002634.1	Q6IB04
	PIGF	NM_173074.3		c.224A>T	p.His75Leu	missense	Exon 2 of 7	NP_775097.1	Q07326-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIGF	ENST00000281382.11	TSL:1 MANE Select	c.224A>T	p.His75Leu	missense	Exon 2 of 6	ENSP00000281382.6	Q07326-1
PIGF	ENST00000306465.8	TSL:1	c.224A>T	p.His75Leu	missense	Exon 2 of 7	ENSP00000302663.4	Q07326-2
PIGF	ENST00000903157.1		c.224A>T	p.His75Leu	missense	Exon 2 of 6	ENSP00000573216.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.97e-7

AC:

AN:

1254152

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

634102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29378

American (AMR)

AF:

0.00

AC:

AN:

44380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24826

East Asian (EAS)

AF:

0.00

AC:

AN:

38666

South Asian (SAS)

AF:

0.00

AC:

AN:

81922

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5388

European-Non Finnish (NFE)

AF:

0.00000108

AC:

AN:

922978

Other (OTH)

AF:

0.00

AC:

AN:

53334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.072

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.62

M_CAP

Benign

0.0024

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.0

PhyloP100

3.9

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.2

REVEL

Benign

0.12

Sift

Benign

0.082

Sift4G

Benign

0.27

Polyphen

0.0020

Vest4

0.37

MutPred

0.54

Loss of helix (P = 0.0076)

MVP

0.48

MPC

0.0059

ClinPred

0.60

GERP RS

3.4

Varity_R

0.22

gMVP

0.62

Mutation Taster

=62/38

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over