2-190986921-G-A

Position:

chr2-190986921-G-A

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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.71

Variant links:

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]

STAT1 links:

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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 linkuse as main transcript	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 linkuse as main transcript	c.1154C>T	p.Thr385Met	missense_variant	14/25	1	NM_007315.4	ENSP00000354394	P4	P42224-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.6

M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.2

D;D;D;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.77

MutPred

0.64

Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);.;

MVP

0.96

MPC

2.6

ClinPred

0.99

GERP RS

5.4

Varity_R

0.67

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over