rs761523186

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_139276.3(STAT3):​c.1366-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

STAT3
NM_139276.3 intron

Scores

2
Splicing: ADA: 0.02373
2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.44

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • hyper-IgE recurrent infection syndrome 1, autosomal dominant
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
  • STAT3-related early-onset multisystem autoimmune disease
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, ClinGen
  • permanent neonatal diabetes mellitus
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 17-42325072-A-G is Benign according to our data. Variant chr17-42325072-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 227962.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
STAT3NM_139276.3 linkc.1366-11T>C intron_variant Intron 15 of 23 ENST00000264657.10 NP_644805.1 P40763-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STAT3ENST00000264657.10 linkc.1366-11T>C intron_variant Intron 15 of 23 1 NM_139276.3 ENSP00000264657.4 P40763-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152016
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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
GnomAD2 exomes
AF:
0.00000399
AC:
1
AN:
250674
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461344
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
726966
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33474
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86234
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53358
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111614
Other (OTH)
AF:
0.00
AC:
0
AN:
60356
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152016
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74264
show subpopulations
African (AFR)
AF:
0.0000242
AC:
1
AN:
41382
American (AMR)
AF:
0.00
AC:
0
AN:
15230
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10592
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68010
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Mar 16, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

c.1366-11T>C in intron 15 of STAT3: This variant is not expected to have clinica l significance because a T>C change at this position does not diverge from the s plice consensus sequence and is therefore unlikely to impact splicing. It has be en identified in 1/10320 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs761523186). -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function Benign:1
Jun 10, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
9.5
DANN
Benign
0.67
PhyloP100
3.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.024
dbscSNV1_RF
Benign
0.20
SpliceAI score (max)
0.16
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs761523186; hg19: chr17-40477090; API