12-57099819-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_003153.5(STAT6):c.1692C>T(p.Ser564=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,614,198 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (36 hom.)
• Consequence: STAT6 NM_003153.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0290

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-57099819-G-A is Benign according to our data. Variant chr12-57099819-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 719355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57099819-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.029 with no splicing effect.
• BS2: High AC in GnomAd at 661 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT6	NM_003153.5	c.1692C>T	p.Ser564=	synonymous_variant	15/22	ENST00000300134.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT6	ENST00000300134.8	c.1692C>T	p.Ser564=	synonymous_variant	15/22	1	NM_003153.5	P1

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 661 AN: 152228 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00481 AC: 1210 AN: 251298 Hom.: 9 AF XY: 0.00498 AC XY: 677 AN XY: 135836

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00179

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.00454

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00456 AC: 6666 AN: 1461852 Hom.: 36 Cov.: 32 AF XY: 0.00453 AC XY: 3291 AN XY: 727224

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00879

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.0215

Gnomad4 NFE exome AF: 0.00418

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.00434 AC: 661 AN: 152346 Hom.: 4 Cov.: 32 AF XY: 0.00534 AC XY: 398 AN XY: 74500

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00443

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0227

Gnomad4 NFE AF: 0.00419

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00358 Hom.: 1

Bravo AF: 0.00292

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00344

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 25, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	STAT6: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	8.3
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35182390; hg19: chr12-57493602; COSMIC: COSV100272879; COSMIC: COSV100272879;