rs2066805

Variant names:

• chr2-190998175-T-C
• rs2066805
• NM_007315.4:c.633+42A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_007315.4(STAT1):​c.633+42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,585,260 control chromosomes in the GnomAD database, including 1,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (177 hom., cov: 32)
  • Exomes 𝑓: 0.027 (1439 hom.)
• Consequence: STAT1 NM_007315.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.907
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-190998175-T-C is Benign according to our data. Variant chr2-190998175-T-C is described in ClinVar as Benign. ClinVar VariationId is 2628271.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT1	NM_007315.4	c.633+42A>G		intron_variant	Intron 8 of 24	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.633+42A>G		intron_variant	Intron 8 of 24	1	NM_007315.4	ENSP00000354394.4

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4388 AN: 152214 Hom.: 175 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0634

Gnomad SAS AF: 0.0450

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0297

GnomAD2 exomes AF: 0.0515 AC: 12896 AN: 250246 AF XY: 0.0454

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.0307

Gnomad EAS exome AF: 0.0651

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0449

GnomAD4 exome AF: 0.0269 AC: 38584 AN: 1432928 Hom.: 1439 Cov.: 26 AF XY: 0.0267 AC XY: 19106 AN XY: 715034

African (AFR) AF: 0.0108 AC: 356 AN: 32878

American (AMR) AF: 0.198 AC: 8815 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 766 AN: 25950

East Asian (EAS) AF: 0.0500 AC: 1978 AN: 39538

South Asian (SAS) AF: 0.0425 AC: 3641 AN: 85634

European-Finnish (FIN) AF: 0.0113 AC: 597 AN: 52892

Middle Eastern (MID) AF: 0.0298 AC: 169 AN: 5666

European-Non Finnish (NFE) AF: 0.0187 AC: 20305 AN: 1086252

Other (OTH) AF: 0.0329 AC: 1957 AN: 59496

GnomAD4 genome AF: 0.0288 AC: 4394 AN: 152332 Hom.: 177 Cov.: 32 AF XY: 0.0294 AC XY: 2190 AN XY: 74500

African (AFR) AF: 0.0141 AC: 587 AN: 41572

American (AMR) AF: 0.114 AC: 1737 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3472

East Asian (EAS) AF: 0.0630 AC: 327 AN: 5194

South Asian (SAS) AF: 0.0448 AC: 216 AN: 4820

European-Finnish (FIN) AF: 0.0104 AC: 111 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0183 AC: 1248 AN: 68032

Other (OTH) AF: 0.0294 AC: 62 AN: 2110

Alfa AF: 0.0298 Hom.: 46

Bravo AF: 0.0375

Asia WGS AF: 0.0690 AC: 240 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.73
DANN	Benign	0.58
PhyloP100		-0.91
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: rs2066805; hg19: chr2-191862901;