17-42322474-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_139276.3(STAT3):c.1909G>A(p.Val637Met) variant causes a missense change involving the alteration of a conserved nucleotide. 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. V637L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

STAT3
NM_139276.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a domain SH2 (size 90) in uniprot entity STAT3_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_139276.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP2

Missense variant in the STAT3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 82 curated pathogenic missense variants (we use a threshold of 10). The gene has 34 curated benign missense variants. Gene score misZ: 4.9943 (above the threshold of 3.09). Trascript score misZ: 7.3744 (above the threshold of 3.09). GenCC associations: The gene is linked to hyper-IgE recurrent infection syndrome 1, autosomal dominant, STAT3-related early-onset multisystem autoimmune disease, permanent neonatal diabetes mellitus.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

PP5

Variant 17-42322474-C-T is Pathogenic according to our data. Variant chr17-42322474-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 18308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42322474-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3 link	c.1909G>A	p.Val637Met	missense_variant	Exon 21 of 24	ENST00000264657.10	NP_644805.1	P40763-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10 link	c.1909G>A	p.Val637Met	missense_variant	Exon 21 of 24	1	NM_139276.3	ENSP00000264657.4		P40763-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyper-IgE recurrent infection syndrome 1, autosomal dominant

Pathogenic:3Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:17881745). Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21792878, 27799162). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.35). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 17881745, 18706697) and observed in multiple (>3) similarly affected unrelated individuals (PMID: 17881745, 18706697, 21792878). Different missense changes at the same codon (p.Val637Ala, p.Val637Leu) have been reported to be associated with STAT3-related disorder (PMID: 17881745, 20159255). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 18, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Department of Immunology, University Hospital Southampton NHSFT

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Feb 15, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect on transcriptional activity (Zhou et al., 2021); This variant is associated with the following publications: (PMID: 34466250, 17881745, 23659370, 18706697, 25038750, 27167980, 21288777, 22084479, 21792878, 27091139, 26293184, 28983403, 30410549, 31596517, 32047500, 32912316, 32768442, 32915432, 32944025, 32888943, 33717144, 33726816, 33864888, 22751495, 22591296, 32248557, 31737384, 36292796, 27799162, 29402895, 34824272, 23830147) -

Hyper-IgE syndrome

Pathogenic:1

May 16, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The STAT3 c.1909G>A (p.Val637Met) variant involves the alteration of a conserved nucleotide and is located in SH2 domain of the protein. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant has been reported in several patients with Hyper IgE syndrome, including evidences of reported de novo occurrence and cosegregation with disease and is absent in 121926 control chromosomes. Functional studies showed that p.V637M affects the STAT3 function (Tamassia_2010, Giacomelli_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as "pathogenic". -

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

Pathogenic:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 637 of the STAT3 protein (p.Val637Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyper-IgE syndrome (PMID: 17881745, 18706697, 21792878). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18308). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt STAT3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects STAT3 function (PMID: 26384563, 27799162). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;.;D;D;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

1.0

.;D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.3

M;M;.;M;M

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.8

D;.;D;.;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

D;.;D;.;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;.;.;D;D

Vest4

0.56

MutPred

0.98

Gain of disorder (P = 0.0725);Gain of disorder (P = 0.0725);.;Gain of disorder (P = 0.0725);Gain of disorder (P = 0.0725);

MVP

0.95

MPC

2.5

ClinPred

0.99

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.87

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

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