NM_139276.3:c.*1853A>G

Variant names:

• chr17-42313892-T-C
• rs1053005
• NM_139276.3:c.*1853A>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.*1853A>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 0.245 in 232,250 control chromosomes in the GnomAD database, including 7,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5575 hom., cov: 32)
  • Exomes 𝑓: 0.23 (2335 hom.)
• Consequence: STAT3 NM_139276.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.291
• Publications: 72 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, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
• STAT3-related early-onset multisystem autoimmune disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• 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=-0.79).
• BP6: Variant 17-42313892-T-C is Benign according to our data. Variant chr17-42313892-T-C is described in ClinVar as Benign. ClinVar VariationId is 323213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.379 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT3	NM_139276.3	MANE Select	c.*1853A>G		3_prime_UTR	Exon 24 of 24	NP_644805.1	P40763-1
	STAT3	NM_001369512.1		c.*1853A>G		3_prime_UTR	Exon 24 of 24	NP_001356441.1	P40763-1
	STAT3	NM_001369513.1		c.*1853A>G		3_prime_UTR	Exon 24 of 24	NP_001356442.1	P40763-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT3	ENST00000264657.10	TSL:1 MANE Select	c.*1853A>G		3_prime_UTR	Exon 24 of 24	ENSP00000264657.4	P40763-1
	STAT3	ENST00000677421.1		c.*1853A>G		3_prime_UTR	Exon 23 of 23	ENSP00000503599.1	A0A7I2V3V0
	STAT3	ENST00000922766.1		c.*1853A>G		3_prime_UTR	Exon 24 of 24	ENSP00000592825.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38321 AN: 152016 Hom.: 5564 Cov.: 32

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.256

GnomAD4 exome AF: 0.232 AC: 18588 AN: 80116 Hom.: 2335 Cov.: 0 AF XY: 0.235 AC XY: 8665 AN XY: 36918

African (AFR) AF: 0.383 AC: 1458 AN: 3810

American (AMR) AF: 0.140 AC: 342 AN: 2440

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 1401 AN: 5034

East Asian (EAS) AF: 0.355 AC: 4018 AN: 11330

South Asian (SAS) AF: 0.287 AC: 196 AN: 682

European-Finnish (FIN) AF: 0.186 AC: 88 AN: 472

Middle Eastern (MID) AF: 0.265 AC: 129 AN: 486

European-Non Finnish (NFE) AF: 0.191 AC: 9403 AN: 49196

Other (OTH) AF: 0.233 AC: 1553 AN: 6666

GnomAD4 genome AF: 0.252 AC: 38369 AN: 152134 Hom.: 5575 Cov.: 32 AF XY: 0.253 AC XY: 18813 AN XY: 74378

African (AFR) AF: 0.384 AC: 15912 AN: 41480

American (AMR) AF: 0.151 AC: 2307 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1038 AN: 3472

East Asian (EAS) AF: 0.362 AC: 1874 AN: 5176

South Asian (SAS) AF: 0.311 AC: 1497 AN: 4816

European-Finnish (FIN) AF: 0.195 AC: 2067 AN: 10586

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12864 AN: 68000

Other (OTH) AF: 0.259 AC: 546 AN: 2112

Alfa AF: 0.214 Hom.: 14561

Bravo AF: 0.254

Asia WGS AF: 0.389 AC: 1349 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hyper-IgE recurrent infection syndrome 1, autosomal dominant (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.8
DANN	Benign	0.73
PhyloP100		0.29
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: rs1053005; hg19: chr17-40465910; COSMIC: COSV52893581; COSMIC: COSV52893581;