2-191015776-C-G

Variant names:

• chr2-191015776-C-G
• rs1467199
• ENST00000454414.5:c.-2+4424G>C

Variant summary

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

The ENST00000454414.5(STAT1):​c.-2+4424G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 151,890 control chromosomes in the GnomAD database, including 5,828 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 0.27 (5828 hom., cov: 31)
• Consequence: STAT1 ENST00000454414.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0840
• Publications: 20 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=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 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.-2+4424G>C		intron_variant	Intron 1 of 4	4		ENSP00000411398.1
STAT1	ENST00000432058.1	c.-155-2098G>C		intron_variant	Intron 1 of 3	4		ENSP00000416019.1

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40924 AN: 151772 Hom.: 5825 Cov.: 31

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.285

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

GnomAD4 genome AF: 0.270 AC: 40943 AN: 151890 Hom.: 5828 Cov.: 31 AF XY: 0.270 AC XY: 20075 AN XY: 74242

African (AFR) AF: 0.334 AC: 13825 AN: 41356

American (AMR) AF: 0.235 AC: 3594 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 912 AN: 3470

East Asian (EAS) AF: 0.475 AC: 2456 AN: 5166

South Asian (SAS) AF: 0.182 AC: 877 AN: 4824

European-Finnish (FIN) AF: 0.261 AC: 2749 AN: 10542

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15635 AN: 67948

Other (OTH) AF: 0.290 AC: 614 AN: 2116

Alfa AF: 0.227 Hom.: 533

Bravo AF: 0.273

Asia WGS AF: 0.307 AC: 1068 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.2
DANN	Benign	0.73
PhyloP100		0.084

Splicing

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

Other links and lift over

dbSNP: rs1467199; hg19: chr2-191880502;