rs139073416

Positions:

• chr1-26795056-C-A
• chr1-26795056-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_017837.4(PIGV):​c.1022C>A​(p.Ala341Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000905 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A341V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: PIGV NM_017837.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.69

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity PIGV_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_017837.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-26795056-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1287.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862
• PP5: Variant 1-26795056-C-A is Pathogenic according to our data. Variant chr1-26795056-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-26795056-C-A is described in Lovd as [Likely_pathogenic]. Variant chr1-26795056-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGV	NM_017837.4	c.1022C>A	p.Ala341Glu	missense_variant	3/4	ENST00000674202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGV	ENST00000674202.1	c.1022C>A	p.Ala341Glu	missense_variant	3/4		NM_017837.4	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000115 AC: 29 AN: 251478 Hom.: 0 AF XY: 0.0000956 AC XY: 13 AN XY: 135914

Gnomad AFR exome AF: 0.0000615

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: 0.000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.0000894 AC XY: 65 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 1 Pathogenic:8

Pathogenic, criteria provided, single submitter	literature only	Department of Clinical Genetics, Medical University of Lodz	Jul 27, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 11, 2019	Across a selection of the literature, the PIGV c.1022C>A (p.Ala341Glu) missense variant was observed in a total of 17 individuals with hyperphosphatasia with mental retardation syndrome, including in nine in a homozygous state (three of whom were related) and in eight in a compound heterozygous state (two of whom were related). The p.Ala341Glu variant was absent from 350 controls and 4,000 exomes (Krawitz et al. 2010; Horn et al. 2011; Thompson et al. 2012; Horn et al. 2014). The variant is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Functional studies by Krawitz et al. (2010) showed that PIGV-deficient CHO cells transfected with wild type PIGV were able to restore surface expression of marker proteins, but that cells carrying the p.Ala341Glu variant were unable to restore expression. Murakami et al. (2012) produced similar results, and also demonstrated that expression of the p.Ala341Glu variant protein was drastically reduced as compared to wild type. The highest allele frequency reported in the Exome Sequencing Project is 0.00035 in the European American population. Based on the collective evidence, the p.Ala341Glu variant is classified as pathogenic for hyperphosphatasia with intellectual disability syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 11, 2017	This variant was identified comp-het. with Chr1: 27121132; NM_017837.3: c.607C>T; p.(Arg203Cys) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 15, 2023	PS3, PM3_strong, PM2, PM5_supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 30, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2022	Published functional studies demonstrate a damaging effect (Krawitz et al., 2010; Murakami et al., 2012); This variant is associated with the following publications: (PMID: 20802478, 22228761, 24129430, 22315194, 21739589, 28688840, 31980526, 33402532, 31589614, 33144682) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 341 of the PIGV protein (p.Ala341Glu). This variant is present in population databases (rs139073416, gnomAD 0.02%). This missense change has been observed in individuals with hyperphosphatasia mental retardation syndrome (PMID: 20802478, 28688840). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1284). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIGV protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PIGV function (PMID: 20802478). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2013

- -

Hyperphosphatasia-intellectual disability syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 27, 2017

The p.Ala341Glu variant in PIGV has been identified in at least 10 individuals w ith hyperphosphatasia-intellectual disability syndrome (HPMR; Krawitz 2010, Horn 2011, Murakami 2012, Horn 2014), all of whom were either homozygous or compound heterozygous. This variant segregated with disease in at least 2 affected famil y members. It was also identified in 0.02% (30/126708) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; db SNP rs139073416). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . Furthermore, in vitro functional studies provide some evidence that the p.Ala3 41Glu variant may impact protein function (Murakami 2012). In summary, although additional studies are required to fully establish its clinical significance, th e p.Ala341Glu variant is likely pathogenic for hyperphosphatasia-intellectual di sability syndrome inherited in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP1, PS3_Supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N;N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.96	D;D
Vest4		0.85
MVP		0.96
MPC		0.66
ClinPred		0.46	T
GERP RS		4.1
Varity_R		0.64
gMVP		0.89

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: rs139073416; hg19: chr1-27121547;