rs35496504

chr4-508840-G-Achr4-508840-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001127178.3(PIGG):c.771G>A(p.Thr257=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,613,918 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (4 hom.)
• Consequence: PIGG NM_001127178.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.399

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-508840-G-A is Benign according to our data. Variant chr4-508840-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 542902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.399 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00296 (451/152262) while in subpopulation AFR AF= 0.00932 (387/41544). AF 95% confidence interval is 0.00855. There are 1 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 BG,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGG	NM_001127178.3	c.771G>A	p.Thr257=	synonymous_variant	5/13	ENST00000453061.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGG	ENST00000453061.7	c.771G>A	p.Thr257=	synonymous_variant	5/13	1	NM_001127178.3	P4

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 451 AN: 152144 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00934

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000700 AC: 176 AN: 251414 Hom.: 2 AF XY: 0.000500 AC XY: 68 AN XY: 135882

Gnomad AFR exome AF: 0.00991

Gnomad AMR exome AF: 0.000347

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000268 AC: 392 AN: 1461656 Hom.: 4 Cov.: 30 AF XY: 0.000220 AC XY: 160 AN XY: 727136

Gnomad4 AFR exome AF: 0.00956

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152262 Hom.: 1 Cov.: 33 AF XY: 0.00306 AC XY: 228 AN XY: 74446

Gnomad4 AFR AF: 0.00932

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00364

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PIGG: BP4, BP7, BS2 -

Intellectual disability, autosomal recessive 53 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.89
Dann	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs35496504; hg19: chr4-502629;