18-62045906-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_176787.5(PIGN):ā€‹c.2746A>Gā€‹(p.Thr916Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.71
Variant links:
Genes affected
PIGN (HGNC:8967): (phosphatidylinositol glycan anchor biosynthesis class N) 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 expressed in the endoplasmic reticulum and transfers phosphoethanolamine (EtNP) to the first mannose of the GPI anchor. Two alternatively spliced variants, which encode an identical isoform, have been reported. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27848732).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PIGNNM_176787.5 linkc.2746A>G p.Thr916Ala missense_variant Exon 31 of 31 ENST00000640252.2 NP_789744.1 O95427A0A024R2C3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PIGNENST00000640252.2 linkc.2746A>G p.Thr916Ala missense_variant Exon 31 of 31 1 NM_176787.5 ENSP00000492233.1 O95427
PIGNENST00000400334.7 linkc.2746A>G p.Thr916Ala missense_variant Exon 30 of 30 1 ENSP00000383188.2 O95427
PIGNENST00000638424.1 linkn.*714A>G non_coding_transcript_exon_variant Exon 29 of 29 5 ENSP00000491963.1 A0A1W2PQZ1
PIGNENST00000638424.1 linkn.*714A>G 3_prime_UTR_variant Exon 29 of 29 5 ENSP00000491963.1 A0A1W2PQZ1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
249032
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135096
show subpopulations
Gnomad AFR exome
AF:
0.000259
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461550
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727052
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.000145
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000987
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jul 14, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2746A>G (p.T916A) alteration is located in exon 31 (coding exon 28) of the PIGN gene. This alteration results from a A to G substitution at nucleotide position 2746, causing the threonine (T) at amino acid position 916 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Multiple congenital anomalies-hypotonia-seizures syndrome 1 Uncertain:1
May 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 916 of the PIGN protein (p.Thr916Ala). This variant is present in population databases (rs754732184, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PIGN-related conditions. ClinVar contains an entry for this variant (Variation ID: 946479). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIGN protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.34
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.32
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.90
.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.28
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.72
T
MutationAssessor
Uncertain
2.9
M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.9
.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.
REVEL
Benign
0.13
Sift
Benign
0.047
.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.
Sift4G
Uncertain
0.021
.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.
Polyphen
1.0
D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D
Vest4
0.56
MVP
0.66
MPC
0.20
ClinPred
0.58
D
GERP RS
5.2
Varity_R
0.16
gMVP
0.46

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754732184; hg19: chr18-59713139; API