chr2-46614980-A-G

Position:

• chr2-46614980-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002643.4(PIGF):​c.185T>C​(p.Val62Ala) variant causes a missense change. The variant allele was found at a frequency of 0.011 in 1,599,654 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (99 hom.)
• Consequence: PIGF NM_002643.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.15

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004613459).
• BP6: Variant 2-46614980-A-G is Benign according to our data. Variant chr2-46614980-A-G is described in ClinVar as [Benign]. Clinvar id is 777946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-46614980-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGF	NM_002643.4	c.185T>C	p.Val62Ala	missense_variant	2/6	ENST00000281382.11	NP_002634.1
PIGF	NM_173074.3	c.185T>C	p.Val62Ala	missense_variant	2/7		NP_775097.1
PIGF	XM_011532908.4	c.185T>C	p.Val62Ala	missense_variant	2/7		XP_011531210.1
PIGF	XM_005264369.4	c.185T>C	p.Val62Ala	missense_variant	2/6		XP_005264426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGF	ENST00000281382.11	c.185T>C	p.Val62Ala	missense_variant	2/6	1	NM_002643.4	ENSP00000281382	P1

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1312 AN: 152234 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00855 AC: 2146 AN: 250888 Hom.: 15 AF XY: 0.00908 AC XY: 1232 AN XY: 135616

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00576

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00615

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0112 AC: 16253 AN: 1447302 Hom.: 99 Cov.: 27 AF XY: 0.0111 AC XY: 8033 AN XY: 721056

Gnomad4 AFR exome AF: 0.00166

Gnomad4 AMR exome AF: 0.00644

Gnomad4 ASJ exome AF: 0.00457

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00675

Gnomad4 FIN exome AF: 0.00448

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.00884

GnomAD4 genome AF: 0.00862 AC: 1314 AN: 152352 Hom.: 9 Cov.: 32 AF XY: 0.00796 AC XY: 593 AN XY: 74502

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00901

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.0118 Hom.: 9

Bravo AF: 0.00857

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0142 AC: 122

ExAC AF: 0.00850 AC: 1032

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0156

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PIGF: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.045	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.078
Sift	Benign	0.27	T;T
Sift4G	Benign	0.41	T;D
Polyphen		0.0080	B;B
Vest4		0.20
MVP		0.23
MPC		0.0059
ClinPred		0.0093	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.47

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: rs113562214; hg19: chr2-46842119; COSMIC: COSV53232584; COSMIC: COSV53232584;