rs12942547

Variant names:

• chr17-42375526-A-G
• rs12942547
• NM_139276.3:c.-24+12753T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-42375526-A-G
• chr17-42375526-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_139276.3(STAT3):​c.-24+12753T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 152,052 control chromosomes in the GnomAD database, including 12,615 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 0.40 (12615 hom., cov: 32)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.820
• Publications: 61 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.-24+12753T>C		intron_variant	Intron 1 of 23	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.-24+12753T>C		intron_variant	Intron 1 of 23	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61223 AN: 151934 Hom.: 12580 Cov.: 32

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.411

Gnomad OTH AF: 0.390

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.403 AC: 61308 AN: 152052 Hom.: 12615 Cov.: 32 AF XY: 0.402 AC XY: 29874 AN XY: 74306

African (AFR) AF: 0.421 AC: 17457 AN: 41480

American (AMR) AF: 0.281 AC: 4298 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1411 AN: 3470

East Asian (EAS) AF: 0.417 AC: 2159 AN: 5182

South Asian (SAS) AF: 0.481 AC: 2320 AN: 4822

European-Finnish (FIN) AF: 0.422 AC: 4454 AN: 10550

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.411 AC: 27916 AN: 67956

Other (OTH) AF: 0.397 AC: 839 AN: 2114

Alfa AF: 0.409 Hom.: 18952

Bravo AF: 0.393

Asia WGS AF: 0.521 AC: 1808 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.9
DANN	Benign	0.30
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12942547; hg19: chr17-40527544;