rs3830585

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_139276.3(STAT3):c.1601-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,038 control chromosomes in the GnomAD database, including 53,571 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 12220 hom., cov: 0)

Exomes 𝑓: 0.22 ( 41351 hom. )

Consequence

STAT3
NM_139276.3 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.765

Publications

14 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

STAT3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 17-42323632-G-GA is Benign according to our data. Variant chr17-42323632-G-GA is described in ClinVar as Benign. ClinVar VariationId is 165294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3 link	c.1601-8dupT		splice_region_variant, intron_variant	Intron 17 of 23	ENST00000264657.10	NP_644805.1	P40763-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10 link	c.1601-8_1601-7insT		splice_region_variant, intron_variant	Intron 17 of 23	1	NM_139276.3	ENSP00000264657.4		P40763-1

Frequencies

GnomAD3 genomes

AF:

0.338

AC:

51335

AN:

151992

Hom.:

12179

Cov.:

show subpopulations

Gnomad AFR

AF:

0.675

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.300

Gnomad EAS

AF:

0.362

Gnomad SAS

AF:

0.346

Gnomad FIN

AF:

0.196

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.192

Gnomad OTH

AF:

0.314

GnomAD2 exomes

AF:

0.246

AC:

61687

AN:

250758

AF XY:

0.244

show subpopulations

Gnomad AFR exome

AF:

0.688

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.282

Gnomad EAS exome

AF:

0.346

Gnomad FIN exome

AF:

0.197

Gnomad NFE exome

AF:

0.193

Gnomad OTH exome

AF:

0.229

GnomAD4 exome

AF:

0.220

AC:

320944

AN:

1460928

Hom.:

41351

Cov.:

AF XY:

0.222

AC XY:

161210

AN XY:

726838

show subpopulations

African (AFR)

AF:

0.696

AC:

23278

AN:

33440

American (AMR)

AF:

0.132

AC:

5892

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

7334

AN:

26136

East Asian (EAS)

AF:

0.355

AC:

14069

AN:

39662

South Asian (SAS)

AF:

0.318

AC:

27385

AN:

86220

European-Finnish (FIN)

AF:

0.198

AC:

10566

AN:

53398

Middle Eastern (MID)

AF:

0.296

AC:

1708

AN:

5766

European-Non Finnish (NFE)

AF:

0.194

AC:

215372

AN:

1111290

Other (OTH)

AF:

0.254

AC:

15340

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

12568

25137

37705

50274

62842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7852

15704

23556

31408

39260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.338

AC:

51437

AN:

152110

Hom.:

12220

Cov.:

AF XY:

0.338

AC XY:

25095

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.675

AC:

28013

AN:

41470

American (AMR)

AF:

0.181

AC:

2764

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

1041

AN:

3470

East Asian (EAS)

AF:

0.363

AC:

1880

AN:

5172

South Asian (SAS)

AF:

0.345

AC:

1662

AN:

4820

European-Finnish (FIN)

AF:

0.196

AC:

2075

AN:

10574

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.192

AC:

13069

AN:

68004

Other (OTH)

AF:

0.316

AC:

667

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1398

2796

4194

5592

6990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

470

940

1410

1880

2350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.248

Hom.:

1394

Bravo

AF:

0.349

EpiCase

AF:

0.204

EpiControl

AF:

0.206

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 30, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Benign based on high population prevalence -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Jun 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

STAT3-related early-onset multisystem autoimmune disease

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyper-IgE syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4014795:STAT3-related early-onset multisystem autoimmune disease

Benign:1

Apr 06, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.77

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over