1-26794501-G-C

Variant names:

• chr1-26794501-G-C
• NM_017837.4:c.467G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_017837.4(PIGV):​c.467G>C​(p.Cys156Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C156Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIGV NM_017837.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-26794501-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGV	NM_017837.4	c.467G>C	p.Cys156Ser	missense_variant	Exon 3 of 4	ENST00000674202.1	NP_060307.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGV	ENST00000674202.1	c.467G>C	p.Cys156Ser	missense_variant	Exon 3 of 4		NM_017837.4	ENSP00000501479.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with PIGV-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 156 of the PIGV protein (p.Cys156Ser). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.69	D;D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.1	D;D;D
REVEL	Pathogenic	0.65
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.10	T;T;D
Polyphen		0.71	P;P;.
Vest4		0.48
MutPred		0.82		Loss of catalytic residue at L157 (P = 0.0141);Loss of catalytic residue at L157 (P = 0.0141);Loss of catalytic residue at L157 (P = 0.0141);
MVP		0.94
MPC		0.46
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.63
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-27120992;