NM_176787.5:c.2750C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_176787.5(PIGN):​c.2750C>T​(p.Thr917Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,613,778 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T917T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

PIGN
NM_176787.5 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.93

Publications

2 publications found
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]
PIGN Gene-Disease associations (from GenCC):
  • multiple congenital anomalies-hypotonia-seizures syndrome 1
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet, ClinGen, PanelApp Australia
  • Fryns syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.22913009).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PIGNNM_176787.5 linkc.2750C>T p.Thr917Met 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.2750C>T p.Thr917Met missense_variant Exon 31 of 31 1 NM_176787.5 ENSP00000492233.1 O95427
PIGNENST00000400334.7 linkc.2750C>T p.Thr917Met missense_variant Exon 30 of 30 1 ENSP00000383188.2 O95427
PIGNENST00000638424.1 linkn.*718C>T non_coding_transcript_exon_variant Exon 29 of 29 5 ENSP00000491963.1 A0A1W2PQZ1
PIGNENST00000638424.1 linkn.*718C>T 3_prime_UTR_variant Exon 29 of 29 5 ENSP00000491963.1 A0A1W2PQZ1

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
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:
0.000250
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000153
AC:
38
AN:
249030
AF XY:
0.000155
show subpopulations
Gnomad AFR exome
AF:
0.0000647
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000257
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000196
AC:
286
AN:
1461516
Hom.:
0
Cov.:
31
AF XY:
0.000210
AC XY:
153
AN XY:
727034
show subpopulations
African (AFR)
AF:
0.0000598
AC:
2
AN:
33472
American (AMR)
AF:
0.000179
AC:
8
AN:
44704
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86216
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53398
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.000236
AC:
262
AN:
1111768
Other (OTH)
AF:
0.000182
AC:
11
AN:
60362
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.453
Heterozygous variant carriers
0
12
24
37
49
61
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152262
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74436
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41554
American (AMR)
AF:
0.000261
AC:
4
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5172
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000250
AC:
17
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000262
Hom.:
0
Bravo
AF:
0.000193
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000119
AC:
1
ExAC
AF:
0.000174
AC:
21
EpiCase
AF:
0.000218
EpiControl
AF:
0.000534

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Aug 23, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35982159) -

Nov 15, 2017
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Uncertain:1
Sep 01, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: PIGN c.2750C>T (p.Thr917Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 249030 control chromosomes (gnomAD). The variant, c.2750C>T, has been reported in the literature in an individual affected with autism spectrum disorder (ASD), but without providing supportive evidence for causality (Zhou_2022). This report does not provide unequivocal conclusions about association of the variant with Multiple Congenital Anomalies-Hypotonia Syndrome 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35982159). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1
Dec 28, 2020
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2750C>T (p.T917M) alteration is located in exon 31 (coding exon 28) of the PIGN gene. This alteration results from a C to T substitution at nucleotide position 2750, causing the threonine (T) at amino acid position 917 to be replaced by a methionine (M). The p.T917M alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Multiple congenital anomalies-hypotonia-seizures syndrome 1 Uncertain:1
Sep 06, 2022
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 methionine, which is neutral and non-polar, at codon 917 of the PIGN protein (p.Thr917Met). This variant is present in population databases (rs61755364, gnomAD 0.02%). 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: 586231). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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
0.13
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.33
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.045
T;.;T;T;T;.;.;.;.;.;T;.;.;T;.;T
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
.;.;.;.;.;.;D;.;D;D;.;D;D;.;D;D
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.23
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
2.0
M;.;M;M;M;.;.;.;.;.;M;.;.;M;.;M
PhyloP100
7.9
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-2.0
.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.
REVEL
Benign
0.14
Sift
Uncertain
0.0070
.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.
Sift4G
Uncertain
0.030
.;.;.;D;.;.;.;.;.;.;D;.;.;.;.;.
Polyphen
1.0
D;.;D;D;D;.;.;.;.;.;D;.;.;D;.;D
Vest4
0.32, 0.32
MVP
0.67
MPC
0.084
ClinPred
0.20
T
GERP RS
5.2
Varity_R
0.072
gMVP
0.27
Mutation Taster
=65/35
polymorphism

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

Other links and lift over

dbSNP: rs61755364; hg19: chr18-59713135; API