4-521700-G-A

Position:

• chr4-521700-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.1373G>A​(p.Arg458His) variant causes a missense change. The variant allele was found at a frequency of 0.126 in 1,613,798 control chromosomes in the GnomAD database, including 15,332 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (3146 hom., cov: 33)
  • Exomes 𝑓: 0.12 (12186 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.00

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=0.0043239594).
• BP6: Variant 4-521700-G-A is Benign according to our data. Variant chr4-521700-G-A is described in ClinVar as [Benign]. Clinvar id is 1170159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGG	NM_001127178.3	c.1373G>A	p.Arg458His	missense_variant	8/13	ENST00000453061.7	NP_001120650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGG	ENST00000453061.7	c.1373G>A	p.Arg458His	missense_variant	8/13	1	NM_001127178.3	ENSP00000415203	P4

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27114 AN: 151994 Hom.: 3121 Cov.: 33

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.169

GnomAD3 exomes AF: 0.133 AC: 33318 AN: 251376 Hom.: 2738 AF XY: 0.130 AC XY: 17713 AN XY: 135882

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.0637

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.198

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.121 AC: 176807 AN: 1461686 Hom.: 12186 Cov.: 32 AF XY: 0.121 AC XY: 87926 AN XY: 727138

Gnomad4 AFR exome AF: 0.338

Gnomad4 AMR exome AF: 0.0717

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.232

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.179 AC: 27191 AN: 152112 Hom.: 3146 Cov.: 33 AF XY: 0.177 AC XY: 13168 AN XY: 74364

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.169

Alfa AF: 0.125 Hom.: 3093

Bravo AF: 0.185

TwinsUK AF: 0.107 AC: 398

ALSPAC AF: 0.110 AC: 425

ESP6500AA AF: 0.333 AC: 1467

ESP6500EA AF: 0.115 AC: 987

ExAC AF: 0.138 AC: 16701

Asia WGS AF: 0.175 AC: 607 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2021	- -

Intellectual disability, autosomal recessive 53 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.0
DANN	Benign	0.76
DEOGEN2	Benign	0.011	.;T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.42	T;T;T;T;T
MetaRNN	Benign	0.0043	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	.;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.43	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.55	T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T
Polyphen		0.0	B;B;.;B;B
Vest4		0.069
MPC		0.21
ClinPred		0.0041	T
GERP RS		1.2
Varity_R		0.012
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs13115344; hg19: chr4-515489; COSMIC: COSV56316623; COSMIC: COSV56316623;