17-42313598-T-C

Variant names:

• chr17-42313598-T-C
• rs1053023
• NM_139276.3:c.*2147A>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.*2147A>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 0.251 in 230,022 control chromosomes in the GnomAD database, including 8,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6006 hom., cov: 30)
  • Exomes 𝑓: 0.23 (2313 hom.)
• Consequence: STAT3 NM_139276.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.138
• Publications: 57 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=-0.81).
• BP6: Variant 17-42313598-T-C is Benign according to our data. Variant chr17-42313598-T-C is described in ClinVar as Benign. ClinVar VariationId is 323209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.*2147A>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.*2147A>G		3_prime_UTR_variant	Exon 24 of 24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39382 AN: 151564 Hom.: 5994 Cov.: 30

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.360

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.233 AC: 18223 AN: 78340 Hom.: 2313 Cov.: 0 AF XY: 0.235 AC XY: 8501 AN XY: 36170

African (AFR) AF: 0.410 AC: 1509 AN: 3678

American (AMR) AF: 0.146 AC: 349 AN: 2394

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 1373 AN: 4980

East Asian (EAS) AF: 0.353 AC: 3944 AN: 11160

South Asian (SAS) AF: 0.288 AC: 190 AN: 660

European-Finnish (FIN) AF: 0.184 AC: 71 AN: 386

Middle Eastern (MID) AF: 0.261 AC: 126 AN: 482

European-Non Finnish (NFE) AF: 0.190 AC: 9134 AN: 48084

Other (OTH) AF: 0.234 AC: 1527 AN: 6516

GnomAD4 genome AF: 0.260 AC: 39432 AN: 151682 Hom.: 6006 Cov.: 30 AF XY: 0.261 AC XY: 19313 AN XY: 74106

African (AFR) AF: 0.411 AC: 16964 AN: 41290

American (AMR) AF: 0.154 AC: 2342 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1039 AN: 3472

East Asian (EAS) AF: 0.361 AC: 1850 AN: 5128

South Asian (SAS) AF: 0.314 AC: 1508 AN: 4806

European-Finnish (FIN) AF: 0.195 AC: 2051 AN: 10520

Middle Eastern (MID) AF: 0.236 AC: 68 AN: 288

European-Non Finnish (NFE) AF: 0.189 AC: 12856 AN: 67920

Other (OTH) AF: 0.268 AC: 563 AN: 2098

Alfa AF: 0.174 Hom.: 822

Bravo AF: 0.263

Asia WGS AF: 0.394 AC: 1365 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	-0.81
CADD	Benign	3.5
DANN	Benign	0.46
PhyloP100		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs1053023; hg19: chr17-40465616;