17-42362183-A-G

Variant names:

• chr17-42362183-A-G
• rs744166
• NM_139276.3:c.-23-13644T>C

Variant summary

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

The NM_139276.3(STAT3):​c.-23-13644T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 152,062 control chromosomes in the GnomAD database, including 18,762 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 0.48 (18762 hom., cov: 32)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890
• Publications: 243 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT3	NM_139276.3	MANE Select	c.-23-13644T>C		intron	N/A	NP_644805.1
	STAT3	NM_001369512.1		c.-1-13666T>C		intron	N/A	NP_001356441.1
	STAT3	NM_001369513.1		c.-4-13663T>C		intron	N/A	NP_001356442.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT3	ENST00000264657.10	TSL:1 MANE Select	c.-23-13644T>C		intron	N/A	ENSP00000264657.4
	STAT3	ENST00000588969.5	TSL:1	c.-1-13666T>C		intron	N/A	ENSP00000467985.1
	STAT3	ENST00000404395.3	TSL:1	c.-1-13666T>C		intron	N/A	ENSP00000384943.3

Frequencies

GnomAD3 genomes AF: 0.477 AC: 72538 AN: 151946 Hom.: 18718 Cov.: 32

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.446

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

GnomAD4 genome AF: 0.478 AC: 72637 AN: 152062 Hom.: 18762 Cov.: 32 AF XY: 0.475 AC XY: 35269 AN XY: 74324

African (AFR) AF: 0.678 AC: 28125 AN: 41470

American (AMR) AF: 0.310 AC: 4731 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1416 AN: 3468

East Asian (EAS) AF: 0.416 AC: 2151 AN: 5174

South Asian (SAS) AF: 0.488 AC: 2352 AN: 4824

European-Finnish (FIN) AF: 0.422 AC: 4465 AN: 10580

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27987 AN: 67958

Other (OTH) AF: 0.453 AC: 955 AN: 2108

Alfa AF: 0.432 Hom.: 67293

Bravo AF: 0.478

Asia WGS AF: 0.536 AC: 1863 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.50
PhyloP100		0.089
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: rs744166; hg19: chr17-40514201;