20-45418853-G-T

Variant names:

• chr20-45418853-G-T
• rs141420243
• NM_015937.6:c.367G>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_015937.6(PIGT):​c.367G>T​(p.Val123Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,613,926 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (76 hom.)
• Consequence: PIGT NM_015937.6 missense, splice_region
• Scores: Splicing: ADA: 0.9778
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.73
• Publications: 13 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 20-45418853-G-T is Benign according to our data. Variant chr20-45418853-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 252704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00597 (909/152300) while in subpopulation AMR AF = 0.00908 (139/15304). AF 95% confidence interval is 0.00785. There are 8 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGT	NM_015937.6	MANE Select	c.367G>T	p.Val123Leu	missense splice_region	Exon 3 of 12	NP_057021.2
	PIGT	NM_001184729.3		c.367G>T	p.Val123Leu	missense splice_region	Exon 3 of 11	NP_001171658.1
	PIGT	NR_047691.2		n.343G>T		splice_region non_coding_transcript_exon	Exon 3 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIGT	ENST00000279036.12	TSL:1 MANE Select	c.367G>T	p.Val123Leu	missense splice_region	Exon 3 of 12	ENSP00000279036.6
	PIGT	ENST00000372689.9	TSL:1	c.367G>T	p.Val123Leu	missense splice_region	Exon 3 of 11	ENSP00000361774.4
	PIGT	ENST00000638489.1	TSL:1	c.337G>T	p.Val113Leu	missense splice_region	Exon 3 of 8	ENSP00000491566.1

Frequencies

GnomAD3 genomes AF: 0.00598 AC: 910 AN: 152182 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00909

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00618 AC: 1553 AN: 251486 AF XY: 0.00602

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.0456

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00692

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00755 AC: 11040 AN: 1461626 Hom.: 76 Cov.: 31 AF XY: 0.00727 AC XY: 5283 AN XY: 727116

African (AFR) AF: 0.00105 AC: 35 AN: 33476

American (AMR) AF: 0.00514 AC: 230 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 1237 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000823 AC: 71 AN: 86242

European-Finnish (FIN) AF: 0.00159 AC: 85 AN: 53400

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.00788 AC: 8762 AN: 1111822

Other (OTH) AF: 0.0101 AC: 608 AN: 60384

GnomAD4 genome AF: 0.00597 AC: 909 AN: 152300 Hom.: 8 Cov.: 32 AF XY: 0.00584 AC XY: 435 AN XY: 74458

African (AFR) AF: 0.00188 AC: 78 AN: 41564

American (AMR) AF: 0.00908 AC: 139 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00707 AC: 481 AN: 68026

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00790 Hom.: 21

Bravo AF: 0.00635

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00521 AC: 632

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Mar 08, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIGT: BS2

Jun 23, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Multiple congenital anomalies-hypotonia-seizures syndrome 3 Benign:2

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Oct 16, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIGT-related disorder Benign:1

Jul 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.0	T
PhyloP100		7.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.17
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		0.11	B
Vest4		0.76
MutPred		0.76		Loss of methylation at K128 (P = 0.084)
MVP		0.32
MPC		0.26
ClinPred		0.022	T
GERP RS		5.8
Varity_R		0.32
gMVP		0.71
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs141420243; hg19: chr20-44047493; COSMIC: COSV99648767; COSMIC: COSV99648767;