rs142192097

Positions:

• chr1-26794383-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017837.4(PIGV):​c.349A>G​(p.Ile117Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,614,180 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: PIGV NM_017837.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 0.325

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0114851).
• BP6: Variant 1-26794383-A-G is Benign according to our data. Variant chr1-26794383-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 297116.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}. Variant chr1-26794383-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000939 (143/152288) while in subpopulation NFE AF= 0.00154 (105/68034). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 59 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	UniProt
PIGV	NM_017837.4	c.349A>G	p.Ile117Val	missense_variant	3/4	ENST00000674202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGV	ENST00000674202.1	c.349A>G	p.Ile117Val	missense_variant	3/4		NM_017837.4	P1

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 251466 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: 2482 AN: 1461892 Hom.: 4 Cov.: 34 AF XY: 0.00166 AC XY: 1209 AN XY: 727248

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: 0.00202

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74462

Gnomad4 AFR AF: 0.000337

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: 0.00188 Hom.: 0

Bravo AF: 0.00104

ExAC AF: 0.00158 AC: 192

EpiCase AF: 0.00196

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hyperphosphatasia with intellectual disability syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 18, 2020	- -

not specified Uncertain:1

Uncertain significance, 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: See c.348G>A. These two variants result in c.348_349delinsAG. (p.Ile117Val). Not reported. MAF 0.25%. Gene is associated with AR hyperphosphatasia with mental retardation syndrome. Severe end of the spectrum presents with multiple congenital anomalies, including Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations. Developmental delays, particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found. VUS3, but the gene may explain the patient's phenotype, so may report in IBA report. - OB 10/22/15: Decided to not include in the report, since it is a VUS3 in a recessive gene not well-associated with the patient's pehnotype, and the variant is heterozygous. -

PIGV-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 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
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.2
DANN	Benign	0.37
DEOGEN2	Benign	0.30	T;.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.66	N;.;N;.
MutationTaster	Benign	0.67	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.56	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.59	T;T;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.080
MVP		0.74
MPC		0.12
ClinPred		0.0021	T
GERP RS		2.1
Varity_R		0.0095
gMVP		0.15

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: rs142192097; hg19: chr1-27120874;