12-57100014-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_003153.5(STAT6):c.1589G>A(p.Arg530Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: STAT6 NM_003153.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

Genes affected

STAT6 (HGNC:11368): (signal transducer and activator of transcription 6) The protein encoded by this gene is a member of the STAT family of transcription factors. 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 plays a central role in exerting IL4 mediated biological responses. It is found to induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. Knockout studies in mice suggested the roles of this gene in differentiation of T helper 2 (Th2) cells, expression of cell surface markers, and class switch of immunoglobulins. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, STAT6
• BP4: Computational evidence support a benign effect (MetaRNN=0.34127915).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT6	NM_003153.5	c.1589G>A	p.Arg530Gln	missense_variant	14/22	ENST00000300134.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT6	ENST00000300134.8	c.1589G>A	p.Arg530Gln	missense_variant	14/22	1	NM_003153.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249044 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461082 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 726768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

The c.1589G>A (p.R530Q) alteration is located in exon 14 (coding exon 13) of the STAT6 gene. This alteration results from a G to A substitution at nucleotide position 1589, causing the arginine (R) at amino acid position 530 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.;D;D;.;D;.;T
Eigen	Benign	0.057
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.58	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.071	D
MutationAssessor	Benign	0.75	N;.;N;N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.066	T;T;T;T;T;T;.;T
Sift4G	Benign	0.087	T;T;T;T;T;T;.;.
Polyphen		0.57	P;.;P;P;.;P;.;.
Vest4		0.28
MutPred		0.46		Loss of MoRF binding (P = 0.0268);.;Loss of MoRF binding (P = 0.0268);Loss of MoRF binding (P = 0.0268);.;Loss of MoRF binding (P = 0.0268);Loss of MoRF binding (P = 0.0268);.;
MVP		0.95
MPC		0.60
ClinPred		0.45	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs915557232; hg19: chr12-57493797;