rs80158178

Variant names:

• chr20-45419334-G-A
• rs80158178
• NM_015937.6:c.533G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-45419334-G-A
• chr20-45419334-G-C
• chr20-45419334-G-T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 9.35
• Publications: 8 publications found

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]

PIGT Gene-Disease associations (from GenCC):

• multiple congenital anomalies-hypotonia-seizures syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 predictors support a deleterious 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 VariationId is 474456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0954 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015937.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGT	NM_015937.6	MANE Select	c.533G>A	p.Arg178Gln	missense	Exon 4 of 12	NP_057021.2
	PIGT	NM_001184728.3		c.365G>A	p.Arg122Gln	missense	Exon 3 of 11	NP_001171657.1	Q969N2-5
	PIGT	NM_001184729.3		c.533G>A	p.Arg178Gln	missense	Exon 4 of 11	NP_001171658.1	Q969N2-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGT	ENST00000279036.12	TSL:1 MANE Select	c.533G>A	p.Arg178Gln	missense	Exon 4 of 12	ENSP00000279036.6	Q969N2-1
	PIGT	ENST00000372689.9	TSL:1	c.533G>A	p.Arg178Gln	missense	Exon 4 of 11	ENSP00000361774.4	Q969N2-6
	PIGT	ENST00000639235.1	TSL:1	c.422G>A	p.Arg141Gln	missense	Exon 3 of 8	ENSP00000492498.1	A0A1W2PRH2

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

GnomAD2 exomes AF: 0.0170 AC: 4276 AN: 251278 AF XY: 0.0126

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 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

African (AFR) AF: 0.000388 AC: 13 AN: 33478

American (AMR) AF: 0.0978 AC: 4371 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26128

East Asian (EAS) AF: 0.0241 AC: 958 AN: 39698

South Asian (SAS) AF: 0.000870 AC: 75 AN: 86248

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53398

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000183 AC: 203 AN: 1111956

Other (OTH) AF: 0.00290 AC: 175 AN: 60388

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

African (AFR) AF: 0.000601 AC: 25 AN: 41578

American (AMR) AF: 0.0316 AC: 484 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0262 AC: 136 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68016

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00409 Hom.: 75

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Multiple congenital anomalies-hypotonia-seizures syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.38
Sift	Benign	0.045	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
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
Mutation Taster		=61/39	polymorphism (auto)

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

Other links and lift over

dbSNP: rs80158178; hg19: chr20-44047974;