rs139518242

Positions:

• chr4-521195-G-A
• chr4-521195-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001127178.3(PIGG):​c.1254G>A​(p.Thr418=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,614,064 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (18 hom.)
• Consequence: PIGG NM_001127178.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0960

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 4-521195-G-A is Benign according to our data. Variant chr4-521195-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 476314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-521195-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.096 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 18 BG,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGG	NM_001127178.3	c.1254G>A	p.Thr418=	synonymous_variant	7/13	ENST00000453061.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGG	ENST00000453061.7	c.1254G>A	p.Thr418=	synonymous_variant	7/13	1	NM_001127178.3	P4

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152172 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00279 AC: 701 AN: 251482 Hom.: 2 AF XY: 0.00280 AC XY: 380 AN XY: 135914

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00998

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00297 AC: 4340 AN: 1461774 Hom.: 18 Cov.: 31 AF XY: 0.00284 AC XY: 2063 AN XY: 727204

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00318

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00213 AC: 325 AN: 152290 Hom.: 1 Cov.: 33 AF XY: 0.00243 AC XY: 181 AN XY: 74460

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00226 Hom.: 0

Bravo AF: 0.00128

EpiCase AF: 0.00213

EpiControl AF: 0.00196

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	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PIGG: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -

Intellectual disability, autosomal recessive 53 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.4
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs139518242; hg19: chr4-514984; COSMIC: COSV99574527; COSMIC: COSV99574527;