rs3744483

Variant names:

• chr17-42314420-T-C
• rs3744483
• NM_139276.3:c.*1325A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-42314420-T-C
• chr17-42314420-T-G

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.*1325A>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 0.262 in 214,772 control chromosomes in the GnomAD database, including 8,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5905 hom., cov: 27)
  • Exomes 𝑓: 0.25 (2194 hom.)
• Consequence: STAT3 NM_139276.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.22
• Publications: 35 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=-0.83).
• BP6: Variant 17-42314420-T-C is Benign according to our data. Variant chr17-42314420-T-C is described in ClinVar as Benign. ClinVar VariationId is 323223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.*1325A>G		3_prime_UTR_variant	Exon 24 of 24	ENST00000264657.10	NP_644805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT3	ENST00000264657.10	c.*1325A>G		3_prime_UTR_variant	Exon 24 of 24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes AF: 0.270 AC: 38938 AN: 144478 Hom.: 5893 Cov.: 27

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.274

GnomAD4 exome AF: 0.245 AC: 17210 AN: 70202 Hom.: 2194 Cov.: 0 AF XY: 0.247 AC XY: 7990 AN XY: 32366

African (AFR) AF: 0.419 AC: 1384 AN: 3304

American (AMR) AF: 0.152 AC: 322 AN: 2116

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1277 AN: 4422

East Asian (EAS) AF: 0.363 AC: 3731 AN: 10292

South Asian (SAS) AF: 0.301 AC: 179 AN: 594

European-Finnish (FIN) AF: 0.184 AC: 89 AN: 484

Middle Eastern (MID) AF: 0.286 AC: 126 AN: 440

European-Non Finnish (NFE) AF: 0.202 AC: 8647 AN: 42716

Other (OTH) AF: 0.249 AC: 1455 AN: 5834

GnomAD4 genome AF: 0.270 AC: 38987 AN: 144570 Hom.: 5905 Cov.: 27 AF XY: 0.274 AC XY: 19039 AN XY: 69604

African (AFR) AF: 0.425 AC: 16681 AN: 39234

American (AMR) AF: 0.172 AC: 2319 AN: 13456

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1031 AN: 3434

East Asian (EAS) AF: 0.371 AC: 1823 AN: 4920

South Asian (SAS) AF: 0.318 AC: 1465 AN: 4602

European-Finnish (FIN) AF: 0.223 AC: 2004 AN: 8982

Middle Eastern (MID) AF: 0.248 AC: 70 AN: 282

European-Non Finnish (NFE) AF: 0.192 AC: 12845 AN: 66762

Other (OTH) AF: 0.278 AC: 555 AN: 2000

Alfa AF: 0.213 Hom.: 4597

Bravo AF: 0.262

Asia WGS AF: 0.390 AC: 1351 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.69
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs3744483; hg19: chr17-40466438; COSMIC: COSV52888309; COSMIC: COSV52888309;