rs115766555

Positions:

• chr4-521714-C-G

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.1387C>G​(p.Leu463Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,614,134 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: PIGG NM_001127178.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.41

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 (MetaRNN=0.0058028996).
• BP6: Variant 4-521714-C-G is Benign according to our data. Variant chr4-521714-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 476316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 BG,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGG	NM_001127178.3	c.1387C>G	p.Leu463Val	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.1387C>G	p.Leu463Val	missense_variant	8/13	1	NM_001127178.3	ENSP00000415203	P4

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00188 AC: 474 AN: 251462 Hom.: 2 AF XY: 0.00181 AC XY: 246 AN XY: 135916

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00266 AC: 3882 AN: 1461812 Hom.: 8 Cov.: 32 AF XY: 0.00252 AC XY: 1834 AN XY: 727212

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.00325

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00142 AC XY: 106 AN XY: 74476

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00238 Hom.: 0

Bravo AF: 0.00139

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00217 AC: 264

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00231

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PIGG: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual disability, autosomal recessive 53 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.9
DANN	Benign	0.67
DEOGEN2	Benign	0.0069	.;T;T;.;.
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.76	T;T;T;T;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0058	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;L;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.54	N;N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.21	T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T
Polyphen		0.11	B;B;.;B;B
Vest4		0.061
MVP		0.32
MPC		0.17
ClinPred		0.00091	T
GERP RS		-1.0
Varity_R		0.023
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs115766555; hg19: chr4-515503;