rs182522437

chr4-516193-A-Gchr4-516193-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001127178.3(PIGG):c.1114+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,595,816 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (17 hom.)
• Consequence: PIGG NM_001127178.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006062
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.226

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-516193-A-G is Benign according to our data. Variant chr4-516193-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 476312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-516193-A-G is described in Lovd as [Likely_benign].
• 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.1114+8A>G		splice_region_variant, intron_variant		ENST00000453061.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGG	ENST00000453061.7	c.1114+8A>G		splice_region_variant, intron_variant		1	NM_001127178.3	P4

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

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: 0.0129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00278 AC: 699 AN: 251202 Hom.: 2 AF XY: 0.00278 AC XY: 378 AN XY: 135820

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00995

Gnomad NFE exome AF: 0.00406

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00294 AC: 4250 AN: 1443524 Hom.: 17 Cov.: 27 AF XY: 0.00281 AC XY: 2023 AN XY: 719212

Gnomad4 AFR exome AF: 0.000302

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00315

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74468

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.00257

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00227 Hom.: 0

Bravo AF: 0.00132

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 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	PIGG: BP4, BS2 -

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	-0.81
Cadd	Benign	1.1
Dann	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		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: rs182522437; hg19: chr4-509982;