12-57100048-C-G

Position:

• chr12-57100048-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_003153.5(STAT6):​c.1555G>C​(p.Asp519His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT6 NM_003153.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.12

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]

STAT6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-57100048-C-G is Pathogenic according to our data. Variant chr12-57100048-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2582691.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT6	NM_003153.5	c.1555G>C	p.Asp519His	missense_variant	14/22	ENST00000300134.8	NP_003144.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT6	ENST00000300134.8	c.1555G>C	p.Asp519His	missense_variant	14/22	1	NM_003153.5	ENSP00000300134.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyper-IgE syndrome 6, autosomal dominant, with recurrent infections Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;T;T;.;T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D;D;.;.
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.5	L;.;L;L;.;L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.46	N;N;N;N;N;N;.;N
REVEL	Pathogenic	0.71
Sift	Benign	0.086	T;T;T;T;T;T;.;T
Sift4G	Benign	0.094	T;T;T;T;T;T;.;.
Polyphen		1.0	D;.;D;D;.;D;.;.
Vest4		0.58
MutPred		0.62		Gain of MoRF binding (P = 0.0578);.;Gain of MoRF binding (P = 0.0578);Gain of MoRF binding (P = 0.0578);.;Gain of MoRF binding (P = 0.0578);Gain of MoRF binding (P = 0.0578);.;
MVP		0.96
MPC		1.4
ClinPred		0.91	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-57493831; COSMIC: COSV55666936; COSMIC: COSV55666936;