2-46614941-T-C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PIGF NM_002643.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.90

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013887584).
• BP6: Variant 2-46614941-T-C is Benign according to our data. Variant chr2-46614941-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3350303.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGF	NM_002643.4	c.224A>G	p.His75Arg	missense_variant	Exon 2 of 6	ENST00000281382.11	NP_002634.1
PIGF	NM_173074.3	c.224A>G	p.His75Arg	missense_variant	Exon 2 of 7		NP_775097.1
PIGF	XM_011532908.4	c.224A>G	p.His75Arg	missense_variant	Exon 2 of 7		XP_011531210.1
PIGF	XM_005264369.4	c.224A>G	p.His75Arg	missense_variant	Exon 2 of 6		XP_005264426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGF	ENST00000281382.11	c.224A>G	p.His75Arg	missense_variant	Exon 2 of 6	1	NM_002643.4	ENSP00000281382.6

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

GnomAD3 exomes AF: 0.000232 AC: 58 AN: 250018 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135206

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.00347

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000152

Gnomad4 OTH exome AF: 0.000337

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

Gnomad4 AFR AF: 0.00293

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000391 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

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PIGF-related condition Benign:1

Apr 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.039
Sift	Benign	0.34	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;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

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

LitVar

Other links and lift over

dbSNP: rs149499692; hg19: chr2-46842080;