2-46612250-G-C

Variant names:

• chr2-46612250-G-C
• rs370735799
• NM_002643.4:c.415C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002643.4(PIGF):​c.415C>G​(p.Leu139Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000297 in 1,344,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L139L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: PIGF NM_002643.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06
• Publications: 1 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)

ACMG classification

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: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGF	NM_002643.4	c.415C>G	p.Leu139Val	missense_variant	Exon 4 of 6	ENST00000281382.11	NP_002634.1
PIGF	NM_173074.3	c.415C>G	p.Leu139Val	missense_variant	Exon 4 of 7		NP_775097.1
PIGF	XM_011532908.4	c.415C>G	p.Leu139Val	missense_variant	Exon 4 of 7		XP_011531210.1
PIGF	XM_005264369.4	c.415C>G	p.Leu139Val	missense_variant	Exon 4 of 6		XP_005264426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGF	ENST00000281382.11	c.415C>G	p.Leu139Val	missense_variant	Exon 4 of 6	1	NM_002643.4	ENSP00000281382.6

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151424 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.00

GnomAD4 exome AF: 8.38e-7 AC: 1 AN: 1193138 Hom.: 0 Cov.: 17 AF XY: 0.00000169 AC XY: 1 AN XY: 591910

African (AFR) AF: 0.00 AC: 0 AN: 24532

American (AMR) AF: 0.0000477 AC: 1 AN: 20954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21574

East Asian (EAS) AF: 0.00 AC: 0 AN: 30526

South Asian (SAS) AF: 0.00 AC: 0 AN: 58056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4138

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 937966

Other (OTH) AF: 0.00 AC: 0 AN: 49440

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151424 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73886

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

African (AFR) AF: 0.0000485 AC: 2 AN: 41218

American (AMR) AF: 0.0000657 AC: 1 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.023284), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.044	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.37	N;N
PhyloP100		3.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.053
Sift	Benign	0.72	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.013	B;B
Vest4		0.30
MutPred		0.39		Gain of MoRF binding (P = 0.1216);Gain of MoRF binding (P = 0.1216);
MVP		0.19
MPC		0.0066
ClinPred		0.37	T
GERP RS		6.0
Varity_R		0.11
gMVP		0.45
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: 1

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

Other links and lift over

dbSNP: rs370735799; hg19: chr2-46839389;