NM_139276.3:c.1261G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong

The NM_139276.3(STAT3):c.1261G>A(p.Gly421Arg) 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

STAT3
NM_139276.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.89

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 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.855

PP5

Variant 17-42329430-C-T is Pathogenic according to our data. Variant chr17-42329430-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224844.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 link	c.1261G>A	p.Gly421Arg	missense_variant	Exon 14 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.1261G>A	p.Gly421Arg	missense_variant	Exon 14 of 24	1	NM_139276.3	ENSP00000264657.4		P40763-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152226

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

STAT3-related early-onset multisystem autoimmune disease

Pathogenic:1

Oct 30, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

segregates with the phenotype in an affected family -

not provided

Pathogenic:1

Apr 11, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G421R variant has been published previously in association with STAT3-related disorders (Milner et al., 2015; Khoury et al., 2017). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). G421R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we consider this variant to be likely pathogenic. -

STAT3-related disorder

Pathogenic:1

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a heterozygous change in patients with Early-onset lymphoproliferation and autoimmunity, Immune dysregulation and Evans syndrome (PMID: 25359994, 30092289, 30940614). Flow cytometry analysis of peripheral blood mononuclear cells from a patient showed delayed phosphorylation compared with healthy controls (PMID: 25359994). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1261G>A (p.Gly421Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1261G>A (p.Gly421Arg) variant is classified as Likely Pathogenic. -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant

Pathogenic:1

Oct 02, 2021

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000224844.3, PMID: 30940614 and 25359994, PS1_P). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.653, 3Cnet: 0.951, PP3). Therefore, this variant is classified as likely pathogenic according to th recommendation of ACMG/AMP guideline. -

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

Pathogenic:1

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects STAT3 function (PMID: 25359994). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STAT3 protein function. ClinVar contains an entry for this variant (Variation ID: 224844). This missense change has been observed in individual(s) with clinical features of STAT3 gain of function associated autoimmune disease and/or Evans syndrome (PMID: 25359994, 30940614, 32531373, 32944025). 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 glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 421 of the STAT3 protein (p.Gly421Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.;D;D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Uncertain

0.61

MutationAssessor

Uncertain

2.5

M;M;.;M;M

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.5

N;.;D;.;N

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

D;.;D;.;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

D;.;.;D;D

Vest4

0.90

MutPred

0.54

Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);.;Gain of solvent accessibility (P = 0.0014);Gain of solvent accessibility (P = 0.0014);

MVP

0.92

MPC

2.6

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.52

gMVP

0.77

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