12-57102490-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_003153.5(STAT6):c.1312G>A(p.Val438Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: STAT6 NM_003153.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

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 Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, STAT6
• BP4: Computational evidence support a benign effect (MetaRNN=0.39422974).
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT6	NM_003153.5	c.1312G>A	p.Val438Met	missense_variant	13/22	ENST00000300134.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT6	ENST00000300134.8	c.1312G>A	p.Val438Met	missense_variant	13/22	1	NM_003153.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152128 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000242 AC: 6 AN: 247770 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000411 AC: 60 AN: 1461224 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 726922

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: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152246 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.000119

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

Dec 01, 2022

The c.1312G>A (p.V438M) alteration is located in exon 13 (coding exon 12) of the STAT6 gene. This alteration results from a G to A substitution at nucleotide position 1312, causing the valine (V) at amino acid position 438 to be replaced by a methionine (M). 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	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.;D;D;.;D;.;T
Eigen	Benign	-0.0032
Eigen_PC	Benign	-0.0081
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.098	D
MutationAssessor	Benign	1.4	L;.;L;L;.;L;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;.;N
REVEL	Uncertain	0.48
Sift	Benign	0.035	D;D;D;D;D;D;.;T
Sift4G	Benign	0.064	T;T;T;T;T;T;.;.
Polyphen		0.91	P;.;P;P;.;P;.;.
Vest4		0.28
MutPred		0.68		Loss of stability (P = 0.0605);.;Loss of stability (P = 0.0605);Loss of stability (P = 0.0605);.;Loss of stability (P = 0.0605);Loss of stability (P = 0.0605);.;
MVP		0.91
MPC		1.3
ClinPred		0.58	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.32

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: rs533111994; hg19: chr12-57496273;