rs587777027

Positions:

• chr20-45419348-A-C
• chr20-45419348-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_015937.6(PIGT):​c.547A>C​(p.Thr183Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,800 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PIGT NM_015937.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.71

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 20-45419348-A-C is Pathogenic according to our data. Variant chr20-45419348-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 64649.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-45419348-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIGT	NM_015937.6	c.547A>C	p.Thr183Pro	missense_variant	4/12	ENST00000279036.12	NP_057021.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIGT	ENST00000279036.12	c.547A>C	p.Thr183Pro	missense_variant	4/12	1	NM_015937.6	ENSP00000279036.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Mar 20, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	3.8	H;.;.;H;.;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;.;.;.;.;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;.;.;.;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.
Vest4		0.95
MutPred		0.86		Loss of phosphorylation at T183 (P = 0.0398);.;.;Loss of phosphorylation at T183 (P = 0.0398);Loss of phosphorylation at T183 (P = 0.0398);Loss of phosphorylation at T183 (P = 0.0398);.;.;.;.;
MVP		0.86
MPC		0.65
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.91

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: rs587777027; hg19: chr20-44047988;