chr12-57105459-G-A

Variant names:

• chr12-57105459-G-A
• rs3024954
• NM_003153.5:c.812+9C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003153.5(STAT6):​c.812+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,613,728 control chromosomes in the GnomAD database, including 2,198 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.066 (1143 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (1055 hom.)
• Consequence: STAT6 NM_003153.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• hyper-IgE syndrome 6, autosomal dominant, with recurrent infections

  Inheritance: AD Classification: STRONG Submitted by: ClinGen, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003153.5. 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
	STAT6	NM_003153.5	MANE Select	c.812+9C>T		intron	N/A	NP_003144.3
	STAT6	NM_001178078.2		c.812+9C>T		intron	N/A	NP_001171549.1	P42226-1
	STAT6	NM_001178079.2		c.812+9C>T		intron	N/A	NP_001171550.1	P42226-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT6	ENST00000300134.8	TSL:1 MANE Select	c.812+9C>T		intron	N/A	ENSP00000300134.3	P42226-1
	STAT6	ENST00000556155.5	TSL:1	c.812+9C>T		intron	N/A	ENSP00000451742.1	P42226-1
	STAT6	ENST00000553533.2	TSL:3	c.812+9C>T		intron	N/A	ENSP00000451546.2	H0YJH6

Frequencies

GnomAD3 genomes AF: 0.0664 AC: 10088 AN: 152034 Hom.: 1140 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0417

GnomAD2 exomes AF: 0.0182 AC: 4556 AN: 250880 AF XY: 0.0135

Gnomad AFR exome AF: 0.237

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000811

Gnomad OTH exome AF: 0.00785

GnomAD4 exome AF: 0.00710 AC: 10374 AN: 1461576 Hom.: 1055 Cov.: 31 AF XY: 0.00614 AC XY: 4468 AN XY: 727102

African (AFR) AF: 0.237 AC: 7933 AN: 33472

American (AMR) AF: 0.0144 AC: 645 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 346 AN: 26114

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

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5764

European-Non Finnish (NFE) AF: 0.000358 AC: 398 AN: 1111884

Other (OTH) AF: 0.0156 AC: 942 AN: 60382

GnomAD4 genome AF: 0.0665 AC: 10113 AN: 152152 Hom.: 1143 Cov.: 32 AF XY: 0.0645 AC XY: 4799 AN XY: 74388

African (AFR) AF: 0.231 AC: 9558 AN: 41462

American (AMR) AF: 0.0243 AC: 371 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68002

Other (OTH) AF: 0.0412 AC: 87 AN: 2110

Alfa AF: 0.0353 Hom.: 412

Bravo AF: 0.0752

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.043
DANN	Benign	0.46
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3024954; hg19: chr12-57499242; COSMIC: COSV55669722;