chr1-26790865-G-C

Position:

• chr1-26790865-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017837.4(PIGV):​c.50G>C​(p.Ser17Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIGV NM_017837.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.997

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14839137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGV	NM_017837.4	c.50G>C	p.Ser17Thr	missense_variant	2/4	ENST00000674202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGV	ENST00000674202.1	c.50G>C	p.Ser17Thr	missense_variant	2/4		NM_017837.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461644 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727124

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 11, 2021

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. This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 17 of the PIGV protein (p.Ser17Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PIGV-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.26	.;T;.;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.43	T;.;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.3	.;L;.;L;.
MutationTaster	Benign	0.97	D;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.15	N;N;N;N;N
REVEL	Benign	0.072
Sift	Benign	0.41	T;T;T;T;T
Sift4G	Benign	0.64	T;T;T;T;T
Polyphen		0.12	.;B;.;B;.
Vest4		0.33, 0.35
MVP		0.64
MPC		0.13
ClinPred		0.054	T
GERP RS		0.24
Varity_R		0.040
gMVP		0.22

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: rs773837990; hg19: chr1-27117356;