rs1347377154

Variant names:

• chr4-521151-C-G
• rs1347377154
• NM_001127178.3:c.1210C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-521151-C-G
• chr4-521151-C-T

Variant summary

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

The NM_001127178.3(PIGG):​c.1210C>G​(p.Leu404Val) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.69

Genes affected

PIGG (HGNC:25985): (phosphatidylinositol glycan anchor biosynthesis class G (EMM blood group)) This gene encodes an enzyme involved in glycosylphosphatidylinositol-anchor biosynthesis. The encoded protein, which is localized to the endoplasmic reticulum, is involved in transferring ethanoloamine phosphate to mannose 2 of glycosylphosphatidylinositol species H7 to form species H8. Allelic variants of this gene have been associated with intellectual disability, hypotonia, and early-onset seizures. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

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=0.16207731).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIGG	NM_001127178.3	c.1210C>G	p.Leu404Val	missense_variant	Exon 7 of 13	ENST00000453061.7	NP_001120650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIGG	ENST00000453061.7	c.1210C>G	p.Leu404Val	missense_variant	Exon 7 of 13	1	NM_001127178.3	ENSP00000415203.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal recessive 53 Uncertain:2

Oct 31, 2018

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 with PIGG-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 404 of the PIGG protein (p.Leu404Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. -

Jul 06, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M;M;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.081	T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.21	B;B;.;B;B
Vest4		0.20
MutPred		0.41		Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);.;.;.;
MVP		0.42
MPC		0.21
ClinPred		0.72	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.45

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: rs1347377154; hg19: chr4-514940;