rs143676075

chr1-26797731-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS1

The NM_017837.4(PIGV):c.1369C>T(p.Leu457Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,613,990 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (1 hom.)
• Consequence: PIGV NM_017837.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 2.94

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013949811).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000677 (103/152164) while in subpopulation NFE AF= 0.000867 (59/68030). AF 95% confidence interval is 0.00069. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGV	NM_017837.4	c.1369C>T	p.Leu457Phe	missense_variant	4/4	ENST00000674202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGV	ENST00000674202.1	c.1369C>T	p.Leu457Phe	missense_variant	4/4		NM_017837.4	P1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000875 AC: 220 AN: 251462 Hom.: 0 AF XY: 0.000920 AC XY: 125 AN XY: 135920

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000927 AC: 1355 AN: 1461826 Hom.: 1 Cov.: 32 AF XY: 0.000939 AC XY: 683 AN XY: 727224

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00922

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000889

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000677 AC: 103 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42 AN XY: 74316

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000867

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.000839

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000774 AC: 94

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 19, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2017	A variant of uncertain significance has been identified in the PIGV gene. The L457F variant in the PIGV gene has been reported previously in a heterozygous state in an individual with seizures, developmental delay, hypotonia, dysmorphic facial features, and hyperphosphatasia (Thompson et al., 2012); however, compound heterozygous variants in the PGAP3 gene have also been reported in this individual (Howard et al., 2014). The L457F variant is observed in 87/66738 (0.13%) alleles from individuals of non-Finnish European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L457F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species; however, Phenylalanine is observed at this position in evolution. Functional studies show that the L457F variant in the PIGV gene does not impair the function of the PIGV protein (Howard et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.63	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.15	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.48
MVP		0.86
MPC		0.65
ClinPred		0.12	T
GERP RS		5.4
Varity_R		0.11
gMVP		0.32

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: rs143676075; hg19: chr1-27124222;