2-190977033-G-A

Position:

chr2-190977033-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007315.4(STAT1):c.1874-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,014 control chromosomes in the GnomAD database, including 51,865 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4048 hom., cov: 32)

Exomes 𝑓: 0.25 ( 47817 hom. )

Consequence

STAT1
NM_007315.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00003493

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.225

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 2-190977033-G-A is Benign according to our data. Variant chr2-190977033-G-A is described in ClinVar as [Benign]. Clinvar id is 333264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-190977033-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT1	NM_007315.4 linkuse as main transcript	c.1874-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8 linkuse as main transcript	c.1874-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007315.4	ENSP00000354394	P4	P42224-1

Frequencies

GnomAD3 genomes

AF:

0.222

AC:

33772

AN:

151822

Hom.:

4051

Cov.:

show subpopulations

Gnomad AFR

AF:

0.171

Gnomad AMI

AF:

0.267

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.258

Gnomad EAS

AF:

0.451

Gnomad SAS

AF:

0.183

Gnomad FIN

AF:

0.244

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.245

Gnomad OTH

AF:

0.210

GnomAD3 exomes

AF:

0.226

AC:

56832

AN:

250966

Hom.:

7199

AF XY:

0.229

AC XY:

31052

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.167

Gnomad AMR exome

AF:

0.112

Gnomad ASJ exome

AF:

0.244

Gnomad EAS exome

AF:

0.446

Gnomad SAS exome

AF:

0.179

Gnomad FIN exome

AF:

0.235

Gnomad NFE exome

AF:

0.244

Gnomad OTH exome

AF:

0.227

GnomAD4 exome

AF:

0.249

AC:

364129

AN:

1461074

Hom.:

47817

Cov.:

AF XY:

0.248

AC XY:

179958

AN XY:

726864

show subpopulations

Gnomad4 AFR exome

AF:

0.171

Gnomad4 AMR exome

AF:

0.117

Gnomad4 ASJ exome

AF:

0.245

Gnomad4 EAS exome

AF:

0.487

Gnomad4 SAS exome

AF:

0.176

Gnomad4 FIN exome

AF:

0.236

Gnomad4 NFE exome

AF:

0.255

Gnomad4 OTH exome

AF:

0.242

GnomAD4 genome

AF:

0.222

AC:

33767

AN:

151940

Hom.:

4048

Cov.:

AF XY:

0.220

AC XY:

16341

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.171

Gnomad4 AMR

AF:

0.170

Gnomad4 ASJ

AF:

0.258

Gnomad4 EAS

AF:

0.450

Gnomad4 SAS

AF:

0.183

Gnomad4 FIN

AF:

0.244

Gnomad4 NFE

AF:

0.245

Gnomad4 OTH

AF:

0.213

Alfa

AF:

0.239

Hom.:

5836

Bravo

AF:

0.213

Asia WGS

AF:

0.293

AC:

1019

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.80

DANN

Benign

0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000035

dbscSNV1_RF

Benign

0.0040

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over