chr17-42362183-A-C

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_139276.3(STAT3):c.-23-13644T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890
• Publications: 252 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, ClinGen, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• STAT3-related early-onset multisystem autoimmune disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	STAT3 NM_139276.3	MANE Select	c.-23-13644T>G	intron	Intron 1 of 23	Prot: NP_644805.1 UniProt:
	STAT3 NM_001369512.1		c.-1-13666T>G	intron	Intron 1 of 23	Prot: NP_001356441.1 UniProt:
	STAT3 NM_001369513.1		c.-4-13663T>G	intron	Intron 1 of 23	Prot: NP_001356442.1 UniProt:

STAT3 NM_139276.3

MANE Select

HGVSc / HGVSpc.-23-13644T>G

Exon rankIntron 1 of 23

intron

Prot: NP_644805.1UniProt: P40763-1

STAT3 NM_001369512.1

HGVSc / HGVSpc.-1-13666T>G

Exon rankIntron 1 of 23

intron

Prot: NP_001356441.1UniProt: P40763-1

STAT3 NM_001369513.1

HGVSc / HGVSpc.-4-13663T>G

Exon rankIntron 1 of 23

intron

Prot: NP_001356442.1UniProt: P40763-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	STAT3 ENST00000264657.10	TSL:1MANE Select	c.-23-13644T>G	intron	Intron 1 of 23	Prot: ENSP00000264657.4 UniProt:
	STAT3 ENST00000588969.5	TSL:1	c.-1-13666T>G	intron	Intron 1 of 23	Prot: ENSP00000467985.1 UniProt:
	STAT3 ENST00000404395.3	TSL:1	c.-1-13666T>G	intron	Intron 1 of 23	Prot: ENSP00000384943.3 UniProt:

STAT3 ENST00000264657.10

TSL:1MANE Select

HGVSc / HGVSpc.-23-13644T>G

Exon rankIntron 1 of 23

intron

Prot: ENSP00000264657.4UniProt: P40763-1

STAT3 ENST00000588969.5

TSL:1

HGVSc / HGVSpc.-1-13666T>G

Exon rankIntron 1 of 23

intron

Prot: ENSP00000467985.1UniProt: P40763-1

STAT3 ENST00000404395.3

TSL:1

HGVSc / HGVSpc.-1-13666T>G

Exon rankIntron 1 of 23

intron

Prot: ENSP00000384943.3UniProt: P40763-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	10
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.93
DANN	Benign	0.46
GPN-Star LLR	N/A	2.2
GPN-Star score	N/A	-2.2
PhyloP100	Benign	0.089

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs744166;

hg19: chr17-40514201;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar