NM_139276.3:c.2144+20C>T

Variant names:

• chr17-42317162-G-A
• rs8069115
• NM_139276.3:c.2144+20C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_139276.3(STAT3):​c.2144+20C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00681 in 1,613,918 control chromosomes in the GnomAD database, including 596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (311 hom., cov: 31)
  • Exomes 𝑓: 0.0040 (285 hom.)
• Consequence: STAT3 NM_139276.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.53
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 17-42317162-G-A is Benign according to our data. Variant chr17-42317162-G-A is described in ClinVar as Benign. ClinVar VariationId is 262464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 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.2144+20C>T		intron	N/A	NP_644805.1
	STAT3	NM_001369512.1		c.2144+20C>T		intron	N/A	NP_001356441.1
	STAT3	NM_001369513.1		c.2144+20C>T		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.2144+20C>T		intron	N/A	ENSP00000264657.4
	STAT3	ENST00000588969.5	TSL:1	c.2144+20C>T		intron	N/A	ENSP00000467985.1
	STAT3	ENST00000404395.3	TSL:1	c.2141+20C>T		intron	N/A	ENSP00000384943.3

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5073 AN: 152088 Hom.: 307 Cov.: 31

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0221

GnomAD2 exomes AF: 0.00954 AC: 2395 AN: 251128 AF XY: 0.00704

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.00689

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.00402 AC: 5879 AN: 1461712 Hom.: 285 Cov.: 31 AF XY: 0.00354 AC XY: 2577 AN XY: 727150

African (AFR) AF: 0.125 AC: 4200 AN: 33468

American (AMR) AF: 0.00779 AC: 348 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39696

South Asian (SAS) AF: 0.00200 AC: 172 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5766

European-Non Finnish (NFE) AF: 0.000455 AC: 506 AN: 1111948

Other (OTH) AF: 0.00946 AC: 571 AN: 60390

GnomAD4 genome AF: 0.0336 AC: 5109 AN: 152206 Hom.: 311 Cov.: 31 AF XY: 0.0330 AC XY: 2453 AN XY: 74426

African (AFR) AF: 0.116 AC: 4814 AN: 41508

American (AMR) AF: 0.0124 AC: 190 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68002

Other (OTH) AF: 0.0219 AC: 46 AN: 2104

Alfa AF: 0.0193 Hom.: 59

Bravo AF: 0.0383

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.35
DANN	Benign	0.79
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=98/2	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: rs8069115; hg19: chr17-40469180;