NM_002643.4:c.415C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_002643.4(PIGF):​c.415C>T​(p.Leu139Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 1,344,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: PIGF NM_002643.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-46612250-G-A is Benign according to our data. Variant chr2-46612250-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3353967.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=3.06 with no splicing effect.

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.415C>T	p.Leu139Leu	synonymous	Exon 4 of 6	NP_002634.1	Q6IB04
	PIGF	NM_173074.3		c.415C>T	p.Leu139Leu	synonymous	Exon 4 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.415C>T	p.Leu139Leu	synonymous	Exon 4 of 6	ENSP00000281382.6	Q07326-1
	PIGF	ENST00000306465.8	TSL:1	c.415C>T	p.Leu139Leu	synonymous	Exon 4 of 7	ENSP00000302663.4	Q07326-2
	PIGF	ENST00000903157.1		c.415C>T	p.Leu139Leu	synonymous	Exon 4 of 6	ENSP00000573216.1

Frequencies

GnomAD3 genomes AF: 0.000264 AC: 40 AN: 151424 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000194

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: 0.000456

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000193 AC: 20 AN: 103420 AF XY: 0.000144

Gnomad AFR exome AF: 0.00

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: 0.000431

Gnomad OTH exome AF: 0.000397

GnomAD4 exome AF: 0.000412 AC: 492 AN: 1193114 Hom.: 0 Cov.: 17 AF XY: 0.000380 AC XY: 225 AN XY: 591900

African (AFR) AF: 0.0000815 AC: 2 AN: 24532

American (AMR) AF: 0.00 AC: 0 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: 0.0000689 AC: 4 AN: 58056

European-Finnish (FIN) AF: 0.0000653 AC: 3 AN: 45950

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

European-Non Finnish (NFE) AF: 0.000505 AC: 474 AN: 937944

Other (OTH) AF: 0.000182 AC: 9 AN: 49440

GnomAD4 genome AF: 0.000264 AC: 40 AN: 151424 Hom.: 0 Cov.: 31 AF XY: 0.000325 AC XY: 24 AN XY: 73886

African (AFR) AF: 0.000194 AC: 8 AN: 41218

American (AMR) AF: 0.00 AC: 0 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: 0.000456 AC: 31 AN: 67928

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.000290 Hom.: 0

Bravo AF: 0.000219

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PIGF-related condition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.2
DANN	Benign	0.91
PhyloP100		3.1
Mutation Taster		=99/1	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: rs370735799; hg19: chr2-46839389;