12-57099375-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2

The NM_003153.5(STAT6):​c.1810G>A​(p.Asp604Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000731 in 1,613,992 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: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

STAT6
NM_003153.5 missense

Scores

10
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.050684392).
BS2
High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
STAT6NM_003153.5 linkuse as main transcriptc.1810G>A p.Asp604Asn missense_variant 16/22 ENST00000300134.8 NP_003144.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
STAT6ENST00000300134.8 linkuse as main transcriptc.1810G>A p.Asp604Asn missense_variant 16/221 NM_003153.5 ENSP00000300134 P1P42226-1

Frequencies

GnomAD3 genomes
AF:
0.000237
AC:
36
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.0351
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
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:
0.0000596
AC:
15
AN:
251492
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000967
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000561
AC:
82
AN:
1461874
Hom.:
0
Cov.:
33
AF XY:
0.0000536
AC XY:
39
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.0000665
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000237
AC:
36
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000123
Hom.:
0
Bravo
AF:
0.000317
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 24, 2021The c.1810G>A (p.D604N) alteration is located in exon 16 (coding exon 15) of the STAT6 gene. This alteration results from a G to A substitution at nucleotide position 1810, causing the aspartic acid (D) at amino acid position 604 to be replaced by an asparagine (N). 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
Pathogenic
0.94
BayesDel_addAF
Uncertain
0.051
T
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D;.;D;D;.;D;T;.
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.80
.;.;.;.;T;T;T;.
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.051
T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.2
M;.;M;M;.;M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-4.7
D;D;D;D;D;D;D;.
REVEL
Pathogenic
0.81
Sift
Uncertain
0.013
D;T;D;D;T;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;.
Polyphen
1.0
D;.;D;D;.;D;.;.
Vest4
0.54
MVP
0.99
MPC
1.3
ClinPred
0.65
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.81
gMVP
0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs373679457; hg19: chr12-57493158; API