rs2291281

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_139276.3(STAT3):c.273+126C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,402,786 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00042 ( 6 hom. )

Consequence

STAT3
NM_139276.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.163

Publications

4 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
STAT3-related early-onset multisystem autoimmune disease
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000302 (46/152282) while in subpopulation EAS AF = 0.00887 (46/5184). AF 95% confidence interval is 0.00684. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 46 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139276.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
STAT3	NM_139276.3	MANE Select	c.273+126C>T	intron	N/A	NP_644805.1	P40763-1
STAT3	NM_001369512.1		c.273+126C>T	intron	N/A	NP_001356441.1	P40763-1
STAT3	NM_001369513.1		c.273+126C>T	intron	N/A	NP_001356442.1	P40763-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
STAT3	ENST00000264657.10	TSL:1 MANE Select	c.273+126C>T	intron	N/A	ENSP00000264657.4	P40763-1
STAT3	ENST00000588969.5	TSL:1	c.273+126C>T	intron	N/A	ENSP00000467985.1	P40763-1
STAT3	ENST00000404395.3	TSL:1	c.273+126C>T	intron	N/A	ENSP00000384943.3	P40763-2

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00886

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

GnomAD4 exome

AF:

0.000415

AC:

519

AN:

1250504

Hom.:

AF XY:

0.000387

AC XY:

244

AN XY:

630674

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28628

American (AMR)

AF:

0.00

AC:

AN:

41498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23784

East Asian (EAS)

AF:

0.0131

AC:

505

AN:

38660

South Asian (SAS)

AF:

0.0000381

AC:

AN:

78664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4532

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

938576

Other (OTH)

AF:

0.000206

AC:

AN:

53274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000302

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41572

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00887

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000642

Hom.:

Bravo

AF:

0.000363

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

-0.16

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over