4-499359-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001127178.3(PIGG):c.24C>G(p.Phe8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 1,609,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F8S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0280

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014869392).
• BP6: Variant 4-499359-C-G is Benign according to our data. Variant chr4-499359-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 772758.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGG	NM_001127178.3	c.24C>G	p.Phe8Leu	missense_variant	1/13	ENST00000453061.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGG	ENST00000453061.7	c.24C>G	p.Phe8Leu	missense_variant	1/13	1	NM_001127178.3	P4

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000439 AC: 107 AN: 243852 Hom.: 0 AF XY: 0.000460 AC XY: 61 AN XY: 132606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.000599

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000444 AC: 647 AN: 1457136 Hom.: 0 Cov.: 31 AF XY: 0.000434 AC XY: 315 AN XY: 725098

Gnomad4 AFR exome AF: 0.0000896

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: 0.00257

Gnomad4 NFE exome AF: 0.000458

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74384

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000405 Hom.: 0

Bravo AF: 0.000212

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000503 AC: 61

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 27, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Intellectual disability, autosomal recessive 53 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.21	T;T;D
Sift4G	Benign	0.54	T;T;T
Polyphen		0.032	B;B;B
Vest4		0.41
MutPred		0.47		Loss of glycosylation at S5 (P = 0.0018);Loss of glycosylation at S5 (P = 0.0018);Loss of glycosylation at S5 (P = 0.0018);
MVP		0.21
MPC		0.21
ClinPred		0.20	T
GERP RS		4.4
Varity_R		0.25
gMVP		0.52

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: rs140860254; hg19: chr4-493148;