rs769031989

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP5

The NM_139276.3(STAT3):c.1919A>T(p.Tyr640Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

STAT3
NM_139276.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2O:1

Conservation

PhyloP100: 8.02

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 Likely_pathogenic. Variant got 6 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;

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). The gene has 82 curated pathogenic missense variants (we use a threshold of 10). The gene has 34 curated benign missense variants. GenCC has associacion of the gene with hyper-IgE recurrent infection syndrome 1, autosomal dominant, STAT3-related early-onset multisystem autoimmune disease, permanent neonatal diabetes mellitus.

PP5

Variant 17-42322464-T-A is Pathogenic according to our data. Variant chr17-42322464-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372521.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, other=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT3	NM_139276.3 link	c.1919A>T	p.Tyr640Phe	missense_variant	21/24	ENST00000264657.10	NP_644805.1	P40763-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10 link	c.1919A>T	p.Tyr640Phe	missense_variant	21/24	1	NM_139276.3	ENSP00000264657.4		P40763-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000301

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Malignant lymphoma, large B-cell, diffuse

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department Of Pathology & Laboratory Medicine, University Of Pennsylvania

Dec 04, 2023

Pre-therapy specimen. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 2016

The Y640F variant has been observed as a somatic variant in multiple individuals with lymphocytic leukemia (Koskela et al., 2012; Kristensen et al., 2014; Tanahashi et al., 2016). However, it has not been published in association with Hyper-IgE syndrome to our knowledge. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Y640F 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 within the critical SH2 domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies have shown that Y640F is a gain-of-function variant that leads to increased cell selection (Koskela et al., 2012; KÃ¼Ã§Ã¼k et al., 2015). Therefore, we consider the variant to be pathogenic. -

EBV-positive nodal T- and NK-cell lymphoma

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Pathology, School of Medicine, Fujita Health University

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 22, 2024

Variant summary: STAT3 c.1919A>T (p.Tyr640Phe) results in a conservative amino acid change located in the Src homology 2 (SH2) domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-06 in 1614036 control chromosomes (gnomAD). c.1919A>T has been reported in the literature in individuals affected with features of Autoimmune Disease, Multisystem, Infantile-Onset, 1 (Hadjadj_2019, Leiding_2023). These data indicate that the variant may be associated with disease. The p.Tyr640Phe variant has also been frequently reported as a GoF somatic mutation in individuals affected with lymphoid neoplasms and other cancer phenotypes (see e.g. Pilati_2011, Koskela_2012, Jerez_2012, Jerez_2013, Crescenzo_2015, and in the COSMIC database). Additionally, the variant has been reported in one patient as a somatic variant in a T-lymphocyte subpopulation, which resulted in an aberrant cytokine production by the aberrant T-cell clone with consequential secondary hypereosinophilia; of note, this patient also had a high level of IgE, suggesting that somatic c.1919A>T also may be associated with hyper IgE phenotype (Walker_2016). Multiple functional studies demonstrated that the variant results in a highly increased transcriptional activity of STAT3 even in the absence of IL-6 stimulation, demonstrating that it is a gain-of-function mutation (e.g. Pilati_2011, Koskela_2012, Crescenzo_2015, Bahal_2019, Jagle_2019, Parri_2020, Kasembeli_2023, Brandstoetter_2023). The following publications have been ascertained in the context of this evaluation (PMID: 22591296, 25873174, 21690253, 26702067, 23926297, 22859607, 31737384, 30940614, 32231398, 31770611, 36240433, 36228738, 36630607). ClinVar contains an entry for this variant (Variation ID: 372521). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 25, 2023

This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 640 of the STAT3 protein (p.Tyr640Phe). 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 Evans syndrome as a germline variant. It is also a common somatic variant observed in individuals with T cell large granular lymphocytic leukemia (PMID: 22591296, 30940614). ClinVar contains an entry for this variant (Variation ID: 372521). 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 not expected to disrupt STAT3 protein function. Experimental studies have shown that this missense change affects STAT3 function (PMID: 22591296, 25873174, 29162862, 29180260, 31771617). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.92

D;.;D;D;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

.;D;D;D;D

M_CAP

Benign

0.083

MetaRNN

Uncertain

0.74

D;D;D;D;D

MetaSVM

Uncertain

-0.038

MutationAssessor

Benign

1.3

L;L;.;L;L

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.0

D;.;D;.;D

REVEL

Uncertain

0.64

Sift

Benign

0.15

T;.;T;.;T

Sift4G

Benign

0.32

T;T;T;T;T

Polyphen

0.98

D;.;.;D;D

Vest4

0.56

MutPred

0.89

Loss of ubiquitination at K642 (P = 0.0603);Loss of ubiquitination at K642 (P = 0.0603);.;Loss of ubiquitination at K642 (P = 0.0603);Loss of ubiquitination at K642 (P = 0.0603);

MVP

0.82

MPC

2.4

ClinPred

0.92

GERP RS

4.6

Varity_R

0.75

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