Genetic Variant STAT6:c.*646A>G (chr12-57095926-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003153.5(STAT6):c.*646A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0803 in 152,468 control chromosomes in the GnomAD database, including 575 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 0.080 ( 574 hom., cov: 33)

Exomes 𝑓: 0.082 ( 1 hom. )

Consequence

STAT6
NM_003153.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.97

Publications

84 publications found

Variant links:

Genes affected

STAT6 (HGNC:11368): (signal transducer and activator of transcription 6) The protein encoded by this gene is a member of the STAT family of transcription factors. 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 plays a central role in exerting IL4 mediated biological responses. It is found to induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. Knockout studies in mice suggested the roles of this gene in differentiation of T helper 2 (Th2) cells, expression of cell surface markers, and class switch of immunoglobulins. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

STAT6 Gene-Disease associations (from GenCC):

hyper-IgE syndrome 6, autosomal dominant, with recurrent infections
Inheritance: AD Classification: STRONG Submitted by: ClinGen, PanelApp Australia

STAT6 links:

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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=-0.8).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003153.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
STAT6	NM_003153.5	MANE Select	c.*646A>G	3_prime_UTR	Exon 22 of 22	NP_003144.3
STAT6	NM_001178078.2		c.*646A>G	3_prime_UTR	Exon 22 of 22	NP_001171549.1	P42226-1
STAT6	NM_001178079.2		c.*646A>G	3_prime_UTR	Exon 22 of 22	NP_001171550.1	P42226-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
STAT6	ENST00000300134.8	TSL:1 MANE Select	c.*646A>G	3_prime_UTR	Exon 22 of 22	ENSP00000300134.3	P42226-1
STAT6	ENST00000553533.2	TSL:3	c.*646A>G	3_prime_UTR	Exon 23 of 23	ENSP00000451546.2	H0YJH6
STAT6	ENST00000714374.1		c.*646A>G	3_prime_UTR	Exon 24 of 24	ENSP00000519641.1	H0YJH6

Frequencies

GnomAD3 genomes

AF:

0.0804

AC:

12231

AN:

152168

Hom.:

573

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0460

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0987

Gnomad ASJ

AF:

0.0597

Gnomad EAS

AF:

0.0839

Gnomad SAS

AF:

0.0489

Gnomad FIN

AF:

0.0496

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.105

Gnomad OTH

AF:

0.103

GnomAD4 exome

AF:

0.0824

AC:

AN:

182

Hom.:

Cov.:

AF XY:

0.100

AC XY:

AN XY:

100

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.100

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.100

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0896

AC:

AN:

134

Other (OTH)

AF:

0.0625

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.571

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0803

AC:

12231

AN:

152286

Hom.:

574

Cov.:

AF XY:

0.0784

AC XY:

5840

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0459

AC:

1907

AN:

41562

American (AMR)

AF:

0.0986

AC:

1508

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0597

AC:

207

AN:

3470

East Asian (EAS)

AF:

0.0837

AC:

434

AN:

5184

South Asian (SAS)

AF:

0.0495

AC:

239

AN:

4826

European-Finnish (FIN)

AF:

0.0496

AC:

527

AN:

10618

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.105

AC:

7110

AN:

68016

Other (OTH)

AF:

0.103

AC:

217

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

599

1199

1798

2398

2997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<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:

0.0994

Hom.:

3643

Bravo

AF:

0.0835

Asia WGS

AF:

0.0670

AC:

233

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.3

(source)

DANN

Benign

0.62

PhyloP100

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over