NM_002643.4:c.227A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002643.4(PIGF):c.227A>G(p.Lys76Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000505 in 1,386,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. K76M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

PIGF
NM_002643.4 missense, splice_region

Scores

Splicing: ADA: 0.9946

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.97

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.227A>G	p.Lys76Arg	missense splice_region	Exon 2 of 6	NP_002634.1	Q6IB04
	PIGF	NM_173074.3		c.227A>G	p.Lys76Arg	missense splice_region	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.227A>G	p.Lys76Arg	missense splice_region	Exon 2 of 6	ENSP00000281382.6	Q07326-1
PIGF	ENST00000306465.8	TSL:1	c.227A>G	p.Lys76Arg	missense splice_region	Exon 2 of 7	ENSP00000302663.4	Q07326-2
PIGF	ENST00000903157.1		c.227A>G	p.Lys76Arg	missense splice_region	Exon 2 of 6	ENSP00000573216.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00000801

AC:

AN:

249832

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000324

AC:

AN:

1234132

Hom.:

Cov.:

AF XY:

0.00000320

AC XY:

AN XY:

625246

show subpopulations

African (AFR)

AF:

0.000138

AC:

AN:

28958

American (AMR)

AF:

0.00

AC:

AN:

44372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24670

East Asian (EAS)

AF:

0.00

AC:

AN:

38570

South Asian (SAS)

AF:

0.00

AC:

AN:

81422

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5362

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

904860

Other (OTH)

AF:

0.00

AC:

AN:

52652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.83

M_CAP

Benign

0.0041

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.8

PhyloP100

5.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.0

REVEL

Benign

0.19

Sift

Benign

0.11

Sift4G

Benign

0.096

Polyphen

0.82

Vest4

0.40

MutPred

0.76

Loss of methylation at K76 (P = 0.0085)

MVP

0.36

MPC

0.019

ClinPred

0.93

GERP RS

4.5

Varity_R

0.41

gMVP

0.54

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.24

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over