rs113994139

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM1PM2PM5PP2PP3_ModeratePP5_Moderate

The NM_139276.3(STAT3):c.1909G>T(p.Val637Leu) 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V637A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

STAT3
NM_139276.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P: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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PS1

Transcript NM_139276.3 (STAT3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

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 chr17-42322473-A-G is described in Lovd as [Likely_pathogenic].

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

PP5

Variant 17-42322474-C-A is Pathogenic according to our data. Variant chr17-42322474-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2138014.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-42322474-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT3	NM_139276.3 linkuse as main transcript	c.1909G>T	p.Val637Leu	missense_variant	21/24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10 linkuse as main transcript	c.1909G>T	p.Val637Leu	missense_variant	21/24	1	NM_139276.3	ENSP00000264657	A1	P40763-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 637 of the STAT3 protein (p.Val637Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper-IgE syndrome (PMID: 17881745; Invitae). ClinVar contains an entry for this variant (Variation ID: 2138014). 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 with a negative predictive value of 80%. This variant disrupts the p.Val637 amino acid residue in STAT3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17881745, 21792878, 26384563, 27799162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;.;D;D;.

Eigen

Benign

-0.037

Eigen_PC

Benign

-0.029

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

.;D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.89

D;D;D;D;D

MetaSVM

Uncertain

0.052

MutationAssessor

Benign

1.4

L;L;.;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.7

D;.;D;.;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.013

D;.;D;.;D

Sift4G

Uncertain

0.055

T;T;D;T;T

Polyphen

0.86

P;.;.;P;P

Vest4

0.62

MutPred

0.98

Loss of methylation at K642 (P = 0.1169);Loss of methylation at K642 (P = 0.1169);.;Loss of methylation at K642 (P = 0.1169);Loss of methylation at K642 (P = 0.1169);

MVP

0.98

MPC

2.5

ClinPred

0.98

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.90

gMVP

0.89

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over