2-191014691-T-C

Variant names:

• chr2-191014691-T-C
• rs10208033
• ENST00000454414.5:c.-1-4687A>G

Variant summary

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

The ENST00000454414.5(STAT1):​c.-1-4687A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 152,054 control chromosomes in the GnomAD database, including 19,417 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 0.49 (19417 hom., cov: 32)
• Consequence: STAT1 ENST00000454414.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.896
• Publications: 22 publications found

Genes affected

STAT1 (HGNC:11362): (signal transducer and activator of transcription 1) The protein encoded by this gene is a member of the STAT protein family. 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. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]

STAT1 Gene-Disease associations (from GenCC):

• autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, Orphanet
• immunodeficiency 31B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000454414.5	c.-1-4687A>G		intron_variant	Intron 1 of 4	4		ENSP00000411398.1
STAT1	ENST00000432058.1	c.-155-1013A>G		intron_variant	Intron 1 of 3	4		ENSP00000416019.1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74809 AN: 151936 Hom.: 19387 Cov.: 32

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.517

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.493 AC: 74891 AN: 152054 Hom.: 19417 Cov.: 32 AF XY: 0.490 AC XY: 36398 AN XY: 74336

African (AFR) AF: 0.642 AC: 26625 AN: 41456

American (AMR) AF: 0.518 AC: 7920 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1849 AN: 3468

East Asian (EAS) AF: 0.662 AC: 3418 AN: 5166

South Asian (SAS) AF: 0.406 AC: 1956 AN: 4820

European-Finnish (FIN) AF: 0.374 AC: 3961 AN: 10582

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.405 AC: 27498 AN: 67960

Other (OTH) AF: 0.519 AC: 1096 AN: 2112

Alfa AF: 0.464 Hom.: 3016

Bravo AF: 0.516

Asia WGS AF: 0.533 AC: 1854 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.7
DANN	Benign	0.74
PhyloP100		-0.90
PromoterAI		0.042	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10208033; hg19: chr2-191879417;