rs1277383877

chr20-45421428-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_015937.6(PIGT):c.1079G>T(p.Gly360Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PIGT NM_015937.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.02

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 20-45421428-G-T is Pathogenic according to our data. Variant chr20-45421428-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 451026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-45421428-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGT	NM_015937.6	c.1079G>T	p.Gly360Val	missense_variant	9/12	ENST00000279036.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGT	ENST00000279036.12	c.1079G>T	p.Gly360Val	missense_variant	9/12	1	NM_015937.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 04, 2022	- -

Seizure;C0557874:Global developmental delay Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.1079G>T (p.G360V) alteration is located in coding exon 9 of the PIGT gene. This alteration results from a G to T substitution at nucleotide position 1079, causing the glycine (G) at amino acid position 360 to be replaced by a valine (V). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the PIGT c.1079G>T alteration was not observed, with coverage at this position. However, this patient and all previously reported patients who are homozygous for this alteration are of Somali descent and this may represent a founder variant in the Somali population. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was reported in the homozygous state in two brothers, born to consanguineous parents of Somali descent, with global developmental delay/intellectual disability, hypotonia, seizures, cortical visual impairment, and dysmorphic facial features. Pyramidal tract signs were also reported, which were not previously reported in association with PIGT-related congenital disorder of glycosylation. Additionally, the brothers lacked skeletal, cardiac, and genitourinary defects typically seen (Skauli, 2016). An additional four affected siblings from two consanguineous families of Somali descent were reported to be homozygous for this alteration (Bayat, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.G360 amino acid is conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ A flow cytometry study showed reduction in the level of glycosylphosphatidylinositol (GPI) anchored proteins on the plasma membrane in peripheral leukocytes homozygous for the p.G360V as compared to controls, with a less pronounced deficit in skin fibroblasts (Skauli, 2016). The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.G360V alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 27, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27916860, 32581362, 33726816, 30976099) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.046	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.6	D;D;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.;D;.
Vest4		0.99
MutPred		0.92		Gain of sheet (P = 0.0344);.;.;Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;.;.;.;.;.;
MVP		0.82
MPC		0.64
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1277383877; hg19: chr20-44050068;