rs1064794957

Variant names:

• chr17-42317182-G-A
• rs1064794957
• NM_139276.3:c.2144C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-42317182-G-A
• chr17-42317182-G-C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_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
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• hyper-IgE recurrent infection syndrome 1, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• STAT3-related early-onset multisystem autoimmune disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, ClinGen
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_139276.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 17-42317182-G-A is Pathogenic according to our data. Variant chr17-42317182-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 421171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.2144C>T	p.Pro715Leu	missense_variant, splice_region_variant	Exon 22 of 24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.2144C>T	p.Pro715Leu	missense_variant, splice_region_variant	Exon 22 of 24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251194 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

STAT3-related early-onset multisystem autoimmune disease Pathogenic:2

May 06, 2022

Institute of Medical Genetics, University of Zurich

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2023

Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Inborn genetic diseases Pathogenic:1

Mar 09, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

STAT3-related disorder Pathogenic:1

Aug 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;C4288261:STAT3 gain of function Pathogenic:1

Dec 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 missense change has been observed in individual(s) with STAT3-related conditions (PMID: 28253502, 29330115; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421171). 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. Experimental studies have shown that this missense change affects STAT3 function (PMID: 28253502). For these reasons, this variant has been classified as Pathogenic. -

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

Mar 17, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inherited Immunodeficiency Diseases Pathogenic:1

Jan 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
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	D
LIST_S2	Benign	0.57	.;T;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.9	L;L;.;L;.
PhyloP100		9.1
PrimateAI	Pathogenic	0.82	D
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	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.91
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064794957; hg19: chr17-40469200; COSMIC: COSV106054584;