chr2-190986921-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_007315.4(STAT1):c.1154C>T(p.Thr385Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T385K) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
STAT1
NM_007315.4 missense
NM_007315.4 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 6.71
Genes affected
STAT1 (HGNC:11362): (signal transducer and activator of transcription 1) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-190986921-G-T is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT1. . Gene score misZ 5.1492 (greater than the threshold 3.09). Trascript score misZ 7.0181 (greater than threshold 3.09). GenCC has associacion of gene with Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, immunodeficiency 31B.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.907
PP5
Variant 2-190986921-G-A is Pathogenic according to our data. Variant chr2-190986921-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 144006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-190986921-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| STAT1 | NM_007315.4 | c.1154C>T | p.Thr385Met | missense_variant | 14/25 | ENST00000361099.8 | NP_009330.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| STAT1 | ENST00000361099.8 | c.1154C>T | p.Thr385Met | missense_variant | 14/25 | 1 | NM_007315.4 | ENSP00000354394 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2024 | Reported in published literature in individuals with IPEX-like disease (PMID: 28601685); Published functional studies demonstrate a increased activity, consistent with a gain of function: enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1 (PMID: 23541320, 28601685); Not observed 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: 26604104, 23709754, 32180118, 32706110, 32477911, 24239102, 23534974, 26743090, 25288569, 22730530, 27379765, 27577878, 28597685, 29270166, 29111217, 29259832, 30443250, 30543054, 28601685, 25042743, 23541320, 31805313, 31767209, 31686315, 31019026, 30092289, 32499645, 32581362, 34060650, 33225392, 33027576, 30755392, 32327459, 32888943, 33475942, 33344614, 35874679, 34738677, 37678716, 34333925, 33005702, 34390440, 34645491, 35482138, 35435464, 36881481, 36790564) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 08, 2022 | PP2, PP3, PM2, PS2, PS3, PS4 - |
Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple patients with autosomal dominant immunodeficiency [PMID 22730530, 27379765, 26604104, 28597685, 23541320, 24239102, 27577878, 23534974, 26743090] - |
Hypothyroidism;C0023885:Liver abscess;C0349588:Short stature;C0454644:Delayed speech and language development;C4024599:Chronic oral candidiasis;C4025208:Severe T-cell immunodeficiency;C4316995:Primary hypothyroidism Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | - | - - |
STAT1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 21, 2024 | The STAT1 c.1154C>T variant is predicted to result in the amino acid substitution p.Thr385Met. This variant has been well-documented to be pathogenic for mucocutaneous candidiasis and immunodeficiency (Takezaki et al. 2012. PubMed ID: 22730530; Depner et al. 2015. PubMed ID: 26604104; Ji et al. 2019. PubMed ID: 30755392). This variant is interpreted as pathogenic by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/144006/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | Dec 21, 2022 | - - |
Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 31, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects STAT1 function (PMID: 22730530, 23534974, 23541320, 23709754, 26604104). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 144006). This missense change has been observed in individual(s) with autosomal dominant chronic mucocutaneous candidiasis (PMID: 22730530, 23541320, 23709754, 24239102, 25042743, 26604104, 26743090, 27379765, 28597685). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 385 of the STAT1 protein (p.Thr385Met). - |
Inherited Immunodeficiency Diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2019 | - - |
Bronchiectasis;C0020676:Hypothyroidism;C0338656:Cognitive impairment;C0401151:Chronic diarrhea;C2315100:Failure to thrive;C2711630:Combined immunodeficiency Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;.
Vest4
MutPred
Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at