chr4-88521639-T-C

Position:

chr4-88521639-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001042616.3(PIGY):c.151A>G(p.Ile51Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

PIGY
NM_001042616.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.09

Variant links:

Genes affected

PIGY (HGNC:28213): (phosphatidylinositol glycan anchor biosynthesis class Y) The protein encoded by this gene is part of the GPI-N-acetylglucosaminyltransferase (GIP-GnT) complex which initiates the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is synthesized in the endoplasmic reticulum and serves as an anchor for many surface proteins. Proteins containing GPI anchors can have an important role in cell-cell interactions. The transcript for this gene is bicistronic. The downstream open reading frame encodes this GPI-GnT complex protein, while the upstream open reading frame encodes a protein with unknown function, as represented by GeneID:100996939. [provided by RefSeq, Aug 2012]

PIGY links:

PYURF (HGNC:44317): (PIGY upstream open reading frame) The product of this gene, which is well-conserved, is encoded by the same bicistronic transcript that encodes phosphatidylinositol glycan anchor biosynthesis, class Y, but the two proteins are unrelated. This gene represents the protein encoded by the upstream open reading frame, while the protein encoded by the downstream open reading frame is represented by GeneID:84992. [provided by RefSeq, Aug 2012]

PYURF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11645684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGY	NM_001042616.3 linkuse as main transcript	c.151A>G	p.Ile51Val	missense_variant	2/2	ENST00000527353.2
PYURF	NM_032906.5 linkuse as main transcript	c.*249A>G		3_prime_UTR_variant	2/2	ENST00000273968.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGY	ENST00000527353.2 linkuse as main transcript	c.151A>G	p.Ile51Val	missense_variant	2/2		NM_001042616.3	P1
PYURF	ENST00000273968.5 linkuse as main transcript	c.*249A>G		3_prime_UTR_variant	2/2	1	NM_032906.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000168

AC:

AN:

249540

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135362

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000209

AC:

305

AN:

1461662

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000236

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000164

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000318

Hom.:

Bravo

AF:

0.000204

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000242

AC:

ExAC

AF:

0.000174

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 51 of the PIGY protein (p.Ile51Val). This variant is present in population databases (rs201457617, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PIGY-related conditions. ClinVar contains an entry for this variant (Variation ID: 1031009). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hyperphosphatasia with intellectual disability syndrome 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 02, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.017

Eigen

Benign

0.045

Eigen_PC

Benign

0.065

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.60

M_CAP

Benign

0.0034

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.78

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.39

REVEL

Benign

0.057

Sift

Benign

0.38

Sift4G

Benign

0.36

Vest4

0.19

MVP

0.12

MPC

0.039

ClinPred

0.018

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.074

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over