NM_002643.4:c.224A>G

Variant names:

• chr2-46614941-T-C
• rs149499692
• NM_002643.4:c.224A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002643.4(PIGF):​c.224A>G​(p.His75Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000196 in 1,406,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PIGF NM_002643.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 3.90
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013887584).

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>G	p.His75Arg	missense	Exon 2 of 6	NP_002634.1	Q6IB04
	PIGF	NM_173074.3		c.224A>G	p.His75Arg	missense	Exon 2 of 7	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.224A>G	p.His75Arg	missense	Exon 2 of 6	ENSP00000281382.6	Q07326-1
	PIGF	ENST00000306465.8	TSL:1	c.224A>G	p.His75Arg	missense	Exon 2 of 7	ENSP00000302663.4	Q07326-2
	PIGF	ENST00000903157.1		c.224A>G	p.His75Arg	missense	Exon 2 of 6	ENSP00000573216.1

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000232 AC: 58 AN: 250018 AF XY: 0.000170

Gnomad AFR exome AF: 0.00285

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 142 AN: 1254150 Hom.: 0 Cov.: 18 AF XY: 0.000110 AC XY: 70 AN XY: 634102

African (AFR) AF: 0.00347 AC: 102 AN: 29376

American (AMR) AF: 0.000135 AC: 6 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24826

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38666

South Asian (SAS) AF: 0.00 AC: 0 AN: 81922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5388

European-Non Finnish (NFE) AF: 0.0000152 AC: 14 AN: 922978

Other (OTH) AF: 0.000337 AC: 18 AN: 53334

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000832 AC XY: 62 AN XY: 74508

African (AFR) AF: 0.00293 AC: 122 AN: 41588

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000700 Hom.: 0

Bravo AF: 0.000948

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000255 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	1	PIGF-related condition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.039
Sift	Benign	0.34	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.25
MVP		0.25
MPC		0.0059
ClinPred		0.017	T
GERP RS		3.4
Varity_R		0.12
gMVP		0.55
Mutation Taster		=64/36	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: rs149499692; hg19: chr2-46842080;