chr4-88521682-G-C

Position:

• chr4-88521682-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001042616.3(PIGY):​c.108C>G​(p.Ser36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,530 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PIGY NM_001042616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26557505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGY	NM_001042616.3	c.108C>G	p.Ser36Arg	missense_variant	2/2	ENST00000527353.2	NP_001036081.1
PYURF	NM_032906.5	c.*206C>G		3_prime_UTR_variant	2/2	ENST00000273968.5	NP_116295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGY	ENST00000527353.2	c.108C>G	p.Ser36Arg	missense_variant	2/2	6	NM_001042616.3	ENSP00000432688.1
PYURF	ENST00000273968	c.*206C>G		3_prime_UTR_variant	2/2	1	NM_032906.5	ENSP00000273968.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249740 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135448

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461530 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000193 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 18, 2023

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 36 of the PIGY protein (p.Ser36Arg). This variant is present in population databases (rs753094548, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PIGY-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.54	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.26
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.013	D
Vest4		0.55
MutPred		0.31		Gain of solvent accessibility (P = 4e-04);
MVP		0.24
MPC		0.048
ClinPred		0.52	D
GERP RS		4.0
Varity_R		0.30
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs753094548; hg19: chr4-89442833;