4-88522011-G-A

Position:

• chr4-88522011-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001042616.3(PIGY):​c.-222C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,545,740 control chromosomes in the GnomAD database, including 11,669 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1902 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9767 hom.)
• Consequence: PIGY NM_001042616.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.309

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 4-88522011-G-A is Benign according to our data. Variant chr4-88522011-G-A is described in ClinVar as [Benign]. Clinvar id is 1283753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88522011-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGY	NM_001042616.3	c.-222C>T		5_prime_UTR_premature_start_codon_gain_variant	2/2	ENST00000527353.2	NP_001036081.1
PYURF	NM_032906.5	c.222C>T	p.Asn74Asn	synonymous_variant	2/2	ENST00000273968.5	NP_116295.1
PIGY	NM_001042616.3	c.-222C>T		5_prime_UTR_variant	2/2	ENST00000527353.2	NP_001036081.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGY	ENST00000527353.2	c.-222C>T		5_prime_UTR_premature_start_codon_gain_variant	2/2	6	NM_001042616.3	ENSP00000432688.1
PYURF	ENST00000273968.5	c.222C>T	p.Asn74Asn	synonymous_variant	2/2	1	NM_032906.5	ENSP00000273968.4
PIGY	ENST00000527353.2	c.-222C>T		5_prime_UTR_variant	2/2	6	NM_001042616.3	ENSP00000432688.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22430 AN: 151698 Hom.: 1895 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0735

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.138 AC: 21137 AN: 153426 Hom.: 1792 AF XY: 0.133 AC XY: 10700 AN XY: 80300

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.0749

Gnomad EAS exome AF: 0.175

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.0716

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.112 AC: 156756 AN: 1393926 Hom.: 9767 Cov.: 32 AF XY: 0.112 AC XY: 77215 AN XY: 687024

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.238

Gnomad4 ASJ exome AF: 0.0759

Gnomad4 EAS exome AF: 0.169

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.0712

Gnomad4 NFE exome AF: 0.104

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.148 AC: 22453 AN: 151814 Hom.: 1902 Cov.: 32 AF XY: 0.148 AC XY: 10946 AN XY: 74176

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.201

Gnomad4 ASJ AF: 0.0761

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.0735

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.155

Alfa AF: 0.118 Hom.: 765

Bravo AF: 0.160

Asia WGS AF: 0.170 AC: 593 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.53

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: rs3177413; hg19: chr4-89443162; COSMIC: COSV56751333; COSMIC: COSV56751333;