rs149214040

Variant names:

• chr17-42325046-C-G
• rs149214040
• NM_139276.3:c.1381G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_139276.3(STAT3):​c.1381G>C​(p.Val461Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00193 in 1,614,066 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (71 hom.)
• Consequence: STAT3 NM_139276.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.07
• Publications: 6 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_139276.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010616392).
• BP6: Variant 17-42325046-C-G is Benign according to our data. Variant chr17-42325046-C-G is described in ClinVar as Benign. ClinVar VariationId is 139328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0546 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.1381G>C	p.Val461Leu	missense	Exon 16 of 24	NP_644805.1	P40763-1
	STAT3	NM_001369512.1		c.1381G>C	p.Val461Leu	missense	Exon 16 of 24	NP_001356441.1	P40763-1
	STAT3	NM_001369513.1		c.1381G>C	p.Val461Leu	missense	Exon 16 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.1381G>C	p.Val461Leu	missense	Exon 16 of 24	ENSP00000264657.4	P40763-1
	STAT3	ENST00000588969.5	TSL:1	c.1381G>C	p.Val461Leu	missense	Exon 16 of 24	ENSP00000467985.1	P40763-1
	STAT3	ENST00000404395.3	TSL:1	c.1381G>C	p.Val461Leu	missense	Exon 16 of 24	ENSP00000384943.3	P40763-2

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 920 AN: 152182 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0579

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00677 AC: 1699 AN: 251112 AF XY: 0.00530

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0477

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00734

GnomAD4 exome AF: 0.00150 AC: 2192 AN: 1461766 Hom.: 71 Cov.: 34 AF XY: 0.00130 AC XY: 943 AN XY: 727172

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.0456 AC: 2040 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111924

Other (OTH) AF: 0.00202 AC: 122 AN: 60378

GnomAD4 genome AF: 0.00603 AC: 919 AN: 152300 Hom.: 35 Cov.: 32 AF XY: 0.00751 AC XY: 559 AN XY: 74472

African (AFR) AF: 0.000409 AC: 17 AN: 41564

American (AMR) AF: 0.0578 AC: 883 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.000626 Hom.: 1

Bravo AF: 0.00891

ExAC AF: 0.00424 AC: 515

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Hyper-IgE recurrent infection syndrome 1, autosomal dominant (1)
-	-	1	Hyper-IgE recurrent infection syndrome 1, autosomal dominant;C4288261:STAT3 gain of function (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	0.0014	T
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	0.041
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.56
Sift	Benign	0.11	T
Sift4G	Benign	0.25	T
Polyphen		0.10	B
Vest4		0.61
MVP		0.98
MPC		1.5
ClinPred		0.014	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.86
Mutation Taster		=62/38	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs149214040; hg19: chr17-40477064; COSMIC: COSV52886372;