rs28454778

chr4-500399-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127178.3(PIGG):c.158C>A(p.Ala53Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,611,608 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (22 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.510

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=0.0017834306).
• BP6: Variant 4-500399-C-A is Benign according to our data. Variant chr4-500399-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 376911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00863 (1313/152228) while in subpopulation AFR AF= 0.0301 (1249/41506). AF 95% confidence interval is 0.0287. There are 23 homozygotes in gnomad4. There are 621 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 BG,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGG	NM_001127178.3	c.158C>A	p.Ala53Asp	missense_variant	2/13	ENST00000453061.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGG	ENST00000453061.7	c.158C>A	p.Ala53Asp	missense_variant	2/13	1	NM_001127178.3	P4

Frequencies

GnomAD3 genomes AF: 0.00863 AC: 1313 AN: 152110 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00209 AC: 526 AN: 251194 Hom.: 8 AF XY: 0.00150 AC XY: 204 AN XY: 135768

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000873 AC: 1274 AN: 1459380 Hom.: 22 Cov.: 30 AF XY: 0.000742 AC XY: 539 AN XY: 726124

Gnomad4 AFR exome AF: 0.0295

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000901

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00863 AC: 1313 AN: 152228 Hom.: 23 Cov.: 32 AF XY: 0.00834 AC XY: 621 AN XY: 74438

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00156 Hom.: 1

Bravo AF: 0.00961

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00266 AC: 323

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 02, 2016	- -

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	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.44	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.18	T;T;D
Sift4G	Benign	0.65	T;T;T
Polyphen		0.52	P;B;B
Vest4		0.21
MVP		0.17
MPC		0.25
ClinPred		0.0026	T
GERP RS		1.6
Varity_R		0.11
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28454778; hg19: chr4-494188;