rs149214040

Positions:

chr17-42325046-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_139276.3(STAT3):c.1381G>C(p.Val461Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00193 in 1,614,066 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 71 hom. )

Consequence

STAT3
NM_139276.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.07

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=0.010616392).

BP6

Variant 17-42325046-C-G is Benign according to our data. Variant chr17-42325046-C-G is described in ClinVar as [Benign]. Clinvar id is 139328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42325046-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT3	NM_139276.3 linkuse as main transcript	c.1381G>C	p.Val461Leu	missense_variant	16/24	ENST00000264657.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT3	ENST00000264657.10 linkuse as main transcript	c.1381G>C	p.Val461Leu	missense_variant	16/24	1	NM_139276.3	A1	P40763-1

Frequencies

GnomAD3 genomes

AF:

0.00605

AC:

920

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0579

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00677

AC:

1699

AN:

251112

Hom.:

AF XY:

0.00530

AC XY:

719

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0477

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00734

GnomAD4 exome

AF:

0.00150

AC:

2192

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

943

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.0456

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00202

GnomAD4 genome

AF:

0.00603

AC:

919

AN:

152300

Hom.:

Cov.:

AF XY:

0.00751

AC XY:

559

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.0578

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.000626

Hom.:

Bravo

AF:

0.00891

ExAC

AF:

0.00424

AC:

515

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 18, 2019	The p.Val461Leu variant in STAT3 is classified as benign because it has been identified in 4.7% (1680/35436) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1 -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The STAT3 p.Val461Leu variant was identified in 4 of 6167 proband chromosomes (frequency: 0.000649) from individuals with suspected hematologic malignancies (Morgan_2017_PMID_29296824). The variant was identified in dbSNP (ID: rs149214040) and ClinVar (classified as likely benign by Illumina for Hyper IgE Syndrome, and as benign by Invitae and ARUP Laboratories). The variant was identified in control databases in 1712 of 268022 chromosomes (56 homozygous) at a frequency of 0.006388 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Latino in 1663 of 35104 chromosomes (freq: 0.04737), Other in 42 of 6698 chromosomes (freq: 0.006271), African in 6 of 23606 chromosomes (freq: 0.000254) and European (non-Finnish) in 1 of 117896 chromosomes (freq: 0.000008), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Val461 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 25, 2019	Variant summary: STAT3 c.1381G>C (p.Val461Leu) results in a conservative amino acid change located in the STAT transcription factor, DNA-binding domain (IPR013801) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0068 in 251112 control chromosomes, predominantly at a frequency of 0.048 within the Latino subpopulation in the gnomAD database, including 56 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 22000-fold of the estimated maximal expected allele frequency for a pathogenic variant in STAT3 causing Hyper IgE Syndrome phenotype (2.2e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. Co-occurrences with a pathogenic variant have been reported (STAT3 c.1909G>A, p.V637M; LCA and Sastalla_2017), providing supporting evidence for a benign role. Two ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 20, 2022

- -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

0.0014

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;.;D;D;.

Eigen

Benign

0.041

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D;D;D

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.4

L;L;.;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.6

N;.;N;.;N

REVEL

Uncertain

0.56

Sift

Benign

0.11

T;.;T;.;T

Sift4G

Benign

0.25

T;T;T;T;T

Polyphen

0.10

B;.;.;B;B

Vest4

0.61

MVP

0.98

MPC

1.5

ClinPred

0.014

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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