2-191010027-T-C

Variant names:

• chr2-191010027-T-C
• rs2066798
• NM_007315.4:c.-1-23A>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.-1-23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,613,286 control chromosomes in the GnomAD database, including 352 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 0.027 (175 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (177 hom.)
• Consequence: STAT1 NM_007315.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.649
• Publications: 2 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT1	NM_007315.4	c.-1-23A>G		intron_variant	Intron 2 of 24	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.-1-23A>G		intron_variant	Intron 2 of 24	1	NM_007315.4	ENSP00000354394.4

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4126 AN: 152200 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0930

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00683 AC: 1713 AN: 250720 AF XY: 0.00528

Gnomad AFR exome AF: 0.0924

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000459

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00295 AC: 4308 AN: 1460968 Hom.: 177 Cov.: 31 AF XY: 0.00257 AC XY: 1867 AN XY: 726788

African (AFR) AF: 0.0980 AC: 3278 AN: 33444

American (AMR) AF: 0.00499 AC: 223 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00625 AC: 36 AN: 5764

European-Non Finnish (NFE) AF: 0.000347 AC: 386 AN: 1111482

Other (OTH) AF: 0.00601 AC: 363 AN: 60350

GnomAD4 genome AF: 0.0272 AC: 4136 AN: 152318 Hom.: 175 Cov.: 32 AF XY: 0.0269 AC XY: 2001 AN XY: 74486

African (AFR) AF: 0.0930 AC: 3864 AN: 41544

American (AMR) AF: 0.0135 AC: 207 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68038

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.00966 Hom.: 67

Bravo AF: 0.0315

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.55
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2066798; hg19: chr2-191874753;