rs1064794957

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_Very_Strong

The NM_139276.3(STAT3):c.2144C>T(p.Pro715Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

STAT3
NM_139276.3 missense, splice_region

Scores

Splicing: ADA: 0.9859

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.05

Variant links:

Genes affected

STAT3 (HGNC:11364): (signal transducer and activator of transcription 3) 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. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. This gene also plays a role in regulating host response to viral and bacterial infections. Mutations in this gene are associated with infantile-onset multisystem autoimmune disease and hyper-immunoglobulin E syndrome. [provided by RefSeq, Aug 2020]

STAT3 links:

STAT3 (HGNC:):

STAT3 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT3. . Gene score misZ 4.9943 (greater than the threshold 3.09). Trascript score misZ 7.3744 (greater than threshold 3.09). GenCC has associacion of gene with hyper-IgE recurrent infection syndrome 1, autosomal dominant, STAT3-related early-onset multisystem autoimmune disease, permanent neonatal diabetes mellitus.

PP5

Variant 17-42317182-G-A is Pathogenic according to our data. Variant chr17-42317182-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT3	NM_139276.3 linkuse as main transcript	c.2144C>T	p.Pro715Leu	missense_variant, splice_region_variant	22/24	ENST00000264657.10	NP_644805.1	P40763-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10 linkuse as main transcript	c.2144C>T	p.Pro715Leu	missense_variant, splice_region_variant	22/24	1	NM_139276.3	ENSP00000264657.4		P40763-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

STAT3-related early-onset multisystem autoimmune disease

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics, University of Zurich	May 06, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine	Jan 03, 2023	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate increased STAT3 transcription in vitro (Jagle et al., 2020); This variant is associated with the following publications: (PMID: 29330115, 34875609, 34556655, 30942636, 28780238, 32577366, 30092289, 32499645, 32581362, 28253502, 31770611, 33519826, 31857100, 32888943, 32944850, 33864888, 22751495, 18602572) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2016

- -

STAT3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2024

The STAT3 c.2144C>T variant is predicted to result in the amino acid substitution p.Pro715Leu. This variant has been reported in patients with a range of autoimmune disorders, occurring de novo in at least two patients (Sediva et al. 2017. PubMed ID: 28253502; Baxter et al. 2021. PubMed ID: 33864888; Besnard et al. 2018. PubMed ID: 29330115; Gonzalez-Mancera et al. 2020. PubMed ID: 32577366; Suh et al. 2019. PubMed ID: 30942636; Table S1, Thaventhiran et al. 2020. PubMed ID: 32499645; López et al. 2021. PubMed ID: 34875609). At PreventionGenetics, this variant has been reported de novo in an individual undergoing testing for autoimmune lymphoproliferative syndrome and paternally inherited in an individual with features of STAT3-related disease (Internal Data). An in vitro luciferase reporter assay showed this variant results in gain of function (Jägle et al. 2019. PubMed ID: 31770611). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4014795:STAT3-related early-onset multisystem autoimmune disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 17, 2021

STAT3 NM_139276.2 exon 22 p.Pro715Leu (c.2144C>T): This variant has been reported in the literature in several individuals, including at least one de novo occurence, who presented with autoimmune and immunodeficiency phenotypes, including at least two with clincial diagnoses of Evan's syndrome (Sediva 2017 PMID:28253502, Besnard 2018 PMID:29330115, Forbes 2018 PMID:30092289, Suh 2019 PMID:30942636, Gonzalez-Mancera 2020 PMID:32577366, Jagle 2020 PMID:31770611, Thaventhiran 2020 PMID:32499645). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:421171). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a gain-of-function effect of this variant (Jagle 2020 PMID:31770611). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above. -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 02, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects STAT3 function (PMID: 28253502). 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 421171). This missense change has been observed in individual(s) with STAT3-related conditions (PMID: 28253502, 29330115; Invitae). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 715 of the STAT3 protein (p.Pro715Leu). -

Inherited Immunodeficiency Diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.;T;D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.57

.;T;D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Uncertain

0.56

D;D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.9

L;L;.;L;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.3

N;.;N;.;N

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0050

D;.;D;.;D

Sift4G

Uncertain

0.012

D;D;D;D;D

Polyphen

1.0

D;.;.;D;D

Vest4

0.47

MutPred

0.49

Loss of disorder (P = 0.0425);Loss of disorder (P = 0.0425);.;Loss of disorder (P = 0.0425);.;

MVP

0.95

MPC

1.5

ClinPred

0.86

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.80

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.

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