rs34916638

chr4-527160-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127178.3(PIGG):c.2191G>A(p.Val731Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,613,802 control chromosomes in the GnomAD database, including 472 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (241 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (231 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.51

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030880868).
• BP6: Variant 4-527160-G-A is Benign according to our data. Variant chr4-527160-G-A is described in ClinVar as [Benign]. Clinvar id is 476333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGG	NM_001127178.3	c.2191G>A	p.Val731Ile	missense_variant	10/13	ENST00000453061.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGG	ENST00000453061.7	c.2191G>A	p.Val731Ile	missense_variant	10/13	1	NM_001127178.3	P4

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4931 AN: 152164 Hom.: 240 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.00850 AC: 2122 AN: 249546 Hom.: 105 AF XY: 0.00609 AC XY: 822 AN XY: 134970

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.00635

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000303

Gnomad OTH exome AF: 0.00459

GnomAD4 exome AF: 0.00331 AC: 4840 AN: 1461520 Hom.: 231 Cov.: 32 AF XY: 0.00286 AC XY: 2077 AN XY: 727056

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.00716

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000211

Gnomad4 OTH exome AF: 0.00737

GnomAD4 genome AF: 0.0325 AC: 4942 AN: 152282 Hom.: 241 Cov.: 32 AF XY: 0.0318 AC XY: 2365 AN XY: 74460

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0150 Hom.: 73

Bravo AF: 0.0390

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.111 AC: 488

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0105 AC: 1278

Asia WGS AF: 0.00866 AC: 31 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2021

- -

Intellectual disability, autosomal recessive 53 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.098
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.86	D;D;D;D
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.00028	P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.48	N;N;N;N
REVEL	Benign	0.051
Sift	Benign	0.082	T;T;T;T
Sift4G	Benign	0.65	T;T;T;T
Polyphen		0.43	B;B;.;P
Vest4		0.051
MPC		0.15
ClinPred		0.010	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.034
gMVP		0.29

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: rs34916638; hg19: chr4-520949;