rs80158178

chr20-45419334-G-Achr20-45419334-G-Cchr20-45419334-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1 PP3 BP6_Very_Strong BA1

The NM_015937.6(PIGT):c.533G>A(p.Arg178Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,614,094 control chromosomes in the GnomAD database, including 330 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R178W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (308 hom.)
• Consequence: PIGT NM_015937.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.35

Genes affected

PIGT (HGNC:14938): (phosphatidylinositol glycan anchor biosynthesis class T) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This protein is an essential component of the multisubunit enzyme, GPI transamidase. GPI transamidase mediates GPI anchoring in the endoplasmic reticulum, by catalyzing the transfer of fully assembled GPI units to proteins. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_015937.6
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 20-45419334-G-A is Benign according to our data. Variant chr20-45419334-G-A is described in ClinVar as [Benign]. Clinvar id is 474456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-45419334-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGT	NM_015937.6	c.533G>A	p.Arg178Gln	missense_variant	4/12	ENST00000279036.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGT	ENST00000279036.12	c.533G>A	p.Arg178Gln	missense_variant	4/12	1	NM_015937.6	P1

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152212 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0315

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0262

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.0170 AC: 4276 AN: 251278 Hom.: 250 AF XY: 0.0126 AC XY: 1716 AN XY: 135794

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.0245

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00398 AC: 5819 AN: 1461764 Hom.: 308 Cov.: 31 AF XY: 0.00345 AC XY: 2507 AN XY: 727190

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.0978

Gnomad4 ASJ exome AF: 0.000498

Gnomad4 EAS exome AF: 0.0241

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00457 AC: 696 AN: 152330 Hom.: 22 Cov.: 33 AF XY: 0.00466 AC XY: 347 AN XY: 74488

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.0316

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0262

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00461 Hom.: 26

Bravo AF: 0.00941

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0135 AC: 1641

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple congenital anomalies-hypotonia-seizures syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 25, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0079	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;.;.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D;D;D;D;.;.;.;.;.;.
REVEL	Uncertain	0.38
Sift	Benign	0.045	D;D;T;T;.;.;.;.;.;.
Sift4G	Uncertain	0.043	D;D;T;D;.;.;.;.;.;.
Polyphen		1.0	D;P;.;.;.;.;.;.;.;.
Vest4		0.34
MPC		0.62
ClinPred		0.038	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.54		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80158178; hg19: chr20-44047974;