rs148662665

Positions:

• chr1-26794382-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_017837.4(PIGV):​c.348G>A​(p.Leu116Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,614,246 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L116L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: PIGV NM_017837.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.226

Genes affected

PIGV (HGNC:26031): (phosphatidylinositol glycan anchor biosynthesis class V) This gene encodes a mannosyltransferase enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is a complex glycolipid that functions as a membrane anchor for many proteins and plays a role in multiple cellular processes including protein sorting and signal transduction. The encoded protein is localized to the endoplasmic reticulum and transfers the second mannose to the GPI backbone. Mutations in this gene are associated with hyperphosphatasia cognitive disability syndrome. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Feb 2011]

PIGV (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-26794382-G-A is Benign according to our data. Variant chr1-26794382-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 297115.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.226 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000932 (142/152356) while in subpopulation NFE AF= 0.00154 (105/68038). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGV	NM_017837.4	c.348G>A	p.Leu116Leu	synonymous_variant	3/4	ENST00000674202.1	NP_060307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGV	ENST00000674202.1	c.348G>A	p.Leu116Leu	synonymous_variant	3/4		NM_017837.4	ENSP00000501479.1

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00139 AC: 349 AN: 251458 Hom.: 0 AF XY: 0.00141 AC XY: 191 AN XY: 135918

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00170 AC: 2481 AN: 1461890 Hom.: 4 Cov.: 34 AF XY: 0.00166 AC XY: 1208 AN XY: 727246

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00201

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000778 AC XY: 58 AN XY: 74506

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00167 Hom.: 0

Bravo AF: 0.00104

EpiCase AF: 0.00196

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 1 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jul 12, 2022	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.1% (105/68046) (https://gnomad.broadinstitute.org/variant/1-26794382-G-A?dataset=gnomad_r3). This variant is present in ClinVar, with multiple labs classifying this variant as Likely Benign or Benign (Variation ID:297115). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant is a silent variant and does not change the amino acid, reducing the probability that this variant is disease causing. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PIGV: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent variant (on both ref transcripts) on its own, but it is in cis with c.349A>G variant in this patient (please see IGV screenshot in the case folder). These two variants result in c.348_349delinsAG. (p.Ile117Val). -

PIGV-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.7
DANN	Benign	0.50

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: rs148662665; hg19: chr1-27120873;