rs146620441

Positions:

chr17-42324819-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_139276.3(STAT3):c.1492A>G(p.Ile498Val) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

STAT3
NM_139276.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.98

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 Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.009115428).

BP6

Variant 17-42324819-T-C is Benign according to our data. Variant chr17-42324819-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 542785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000756 (115/152202) while in subpopulation AFR AF= 0.00255 (106/41534). AF 95% confidence interval is 0.00216. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT3	NM_139276.3 linkuse as main transcript	c.1492A>G	p.Ile498Val	missense_variant	17/24	ENST00000264657.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT3	ENST00000264657.10 linkuse as main transcript	c.1492A>G	p.Ile498Val	missense_variant	17/24	1	NM_139276.3	A1	P40763-1

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000243

AC:

AN:

251476

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000105

AC:

154

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00281

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000756

AC:

115

AN:

152202

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00255

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000241

Hom.:

Bravo

AF:

0.00104

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 15, 2022

- -

STAT3 gain of function;CN031130:Hyper-IgE recurrent infection syndrome 1, autosomal dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

STAT3: PP2, BP4, BS1 -

STAT3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Uncertain

0.48

T;.;T;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.82

.;T;T;T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.0091

T;T;T;T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

-0.34

N;N;.;N;N

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

0.59

N;.;N;.;N

REVEL

Benign

0.20

Sift

Benign

0.61

T;.;T;.;T

Sift4G

Benign

0.31

T;T;T;T;T

Polyphen

0.0010

B;.;.;B;B

Vest4

0.15

MVP

0.54

MPC

1.1

ClinPred

0.034

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: 6

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