rs148579497

chr4-539186-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_001127178.3(PIGG):c.2769C>T(p.Tyr923=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,612,896 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: PIGG NM_001127178.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.220

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 Benign. Variant got -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 4-539186-C-T is Benign according to our data. Variant chr4-539186-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 476341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-539186-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.22 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGG	NM_001127178.3	c.2769C>T	p.Tyr923=	synonymous_variant	13/13	ENST00000453061.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGG	ENST00000453061.7	c.2769C>T	p.Tyr923=	synonymous_variant	13/13	1	NM_001127178.3	P4

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000370 AC: 93 AN: 251428 Hom.: 0 AF XY: 0.000375 AC XY: 51 AN XY: 135900

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00446

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1460542 Hom.: 0 Cov.: 29 AF XY: 0.000139 AC XY: 101 AN XY: 726690

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00270

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00424

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000854 Hom.: 0

Bravo AF: 0.000159

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal recessive 53 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2022

- -

PIGG-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	4.0
Dann	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -33

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

Publications

LitVar

Other links and lift over

dbSNP: rs148579497; hg19: chr4-532975;