rs12693590

Variant names:

• chr2-190993910-A-C
• rs12693590
• NM_007315.4:c.944+1151T>G

Variant summary

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

The NM_007315.4(STAT1):​c.944+1151T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0801 in 152,126 control chromosomes in the GnomAD database, including 636 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 0.080 (636 hom., cov: 31)
• Consequence: STAT1 NM_007315.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.675
• Publications: 10 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT1	NM_007315.4	c.944+1151T>G		intron_variant	Intron 10 of 24	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.944+1151T>G		intron_variant	Intron 10 of 24	1	NM_007315.4	ENSP00000354394.4

Frequencies

GnomAD3 genomes AF: 0.0801 AC: 12170 AN: 152008 Hom.: 633 Cov.: 31

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.0714

Gnomad ASJ AF: 0.0975

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0286

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0724

Gnomad OTH AF: 0.0905

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

GnomAD4 genome AF: 0.0801 AC: 12188 AN: 152126 Hom.: 636 Cov.: 31 AF XY: 0.0768 AC XY: 5715 AN XY: 74380

African (AFR) AF: 0.124 AC: 5147 AN: 41470

American (AMR) AF: 0.0712 AC: 1088 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0975 AC: 338 AN: 3468

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4822

European-Finnish (FIN) AF: 0.0286 AC: 303 AN: 10592

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0725 AC: 4927 AN: 68000

Other (OTH) AF: 0.0891 AC: 188 AN: 2110

Alfa AF: 0.0762 Hom.: 962

Bravo AF: 0.0884

Asia WGS AF: 0.0230 AC: 80 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.5
DANN	Benign	0.70
PhyloP100		-0.68
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: rs12693590; hg19: chr2-191858636;