rs745563663

Positions:

• chr4-527176-C-A
• chr4-527176-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001127178.3(PIGG):​c.2207C>A​(p.Ala736Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68

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]

PIGG (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGG	NM_001127178.3	c.2207C>A	p.Ala736Glu	missense_variant	10/13	ENST00000453061.7	NP_001120650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGG	ENST00000453061.7	c.2207C>A	p.Ala736Glu	missense_variant	10/13	1	NM_001127178.3	ENSP00000415203.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248482 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460872 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726676

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;T;T;.
Eigen	Benign	0.092
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;M;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Benign	0.29
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Benign	0.37	T;T;T;T
Polyphen		1.0	D;D;.;D
Vest4		0.85
MutPred		0.70		.;Gain of sheet (P = 0.0827);.;.;
MVP		0.24
MPC		0.74
ClinPred		0.94	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.41
gMVP		0.86

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: rs745563663; hg19: chr4-520965;