rs1053004

Variant names:

• chr17-42314074-G-A
• rs1053004
• NM_139276.3:c.*1671C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-42314074-G-A
• chr17-42314074-G-C
• chr17-42314074-G-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.*1671C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 231,740 control chromosomes in the GnomAD database, including 37,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (22511 hom., cov: 32)
  • Exomes 𝑓: 0.61 (15268 hom.)
• Consequence: STAT3 NM_139276.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82
• Publications: 74 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=-0.91).
• BP6: Variant 17-42314074-G-A is Benign according to our data. Variant chr17-42314074-G-A is described in ClinVar as Benign. ClinVar VariationId is 323218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT3	NM_139276.3	c.*1671C>T		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.*1671C>T		3_prime_UTR_variant	Exon 24 of 24	1	NM_139276.3	ENSP00000264657.4

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74736 AN: 152000 Hom.: 22516 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.539

GnomAD4 exome AF: 0.608 AC: 48423 AN: 79622 Hom.: 15268 Cov.: 0 AF XY: 0.608 AC XY: 22297 AN XY: 36680

African (AFR) AF: 0.119 AC: 448 AN: 3768

American (AMR) AF: 0.712 AC: 1753 AN: 2462

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 3169 AN: 5012

East Asian (EAS) AF: 0.599 AC: 6802 AN: 11356

South Asian (SAS) AF: 0.527 AC: 355 AN: 674

European-Finnish (FIN) AF: 0.639 AC: 106 AN: 166

Middle Eastern (MID) AF: 0.623 AC: 299 AN: 480

European-Non Finnish (NFE) AF: 0.644 AC: 31638 AN: 49098

Other (OTH) AF: 0.583 AC: 3853 AN: 6606

GnomAD4 genome AF: 0.491 AC: 74720 AN: 152118 Hom.: 22511 Cov.: 32 AF XY: 0.493 AC XY: 36648 AN XY: 74368

African (AFR) AF: 0.123 AC: 5121 AN: 41516

American (AMR) AF: 0.693 AC: 10589 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 2152 AN: 3468

East Asian (EAS) AF: 0.606 AC: 3128 AN: 5162

South Asian (SAS) AF: 0.515 AC: 2484 AN: 4824

European-Finnish (FIN) AF: 0.594 AC: 6291 AN: 10586

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.636 AC: 43236 AN: 67978

Other (OTH) AF: 0.533 AC: 1123 AN: 2108

Alfa AF: 0.583 Hom.: 72120

Bravo AF: 0.484

Asia WGS AF: 0.454 AC: 1582 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 12, 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	-0.91
CADD	Benign	0.22
DANN	Benign	0.54
PhyloP100		-1.8
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: rs1053004; hg19: chr17-40466092;