chr2-190995209-C-T

Position:

chr2-190995209-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1PP2BP4_StrongBS1BS2

The NM_007315.4(STAT1):c.796G>A(p.Val266Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,613,894 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0032 ( 15 hom. )

Consequence

STAT1
NM_007315.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:7

Conservation

PhyloP100: 0.630

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:

STAT1 (HGNC:):

STAT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM1

In a coiled_coil_region (size 181) in uniprot entity STAT1_HUMAN there are 33 pathogenic changes around while only 1 benign (97%) in NM_007315.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT1. . Gene score misZ 5.1492 (greater than the threshold 3.09). Trascript score misZ 7.0181 (greater than threshold 3.09). GenCC has associacion of gene with Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, immunodeficiency 31B.

BP4

Computational evidence support a benign effect (MetaRNN=0.014246553).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00241 (367/152142) while in subpopulation NFE AF= 0.00332 (226/68008). AF 95% confidence interval is 0.00297. There are 0 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT1	NM_007315.4 linkuse as main transcript	c.796G>A	p.Val266Ile	missense_variant	10/25	ENST00000361099.8	NP_009330.1	P42224-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8 linkuse as main transcript	c.796G>A	p.Val266Ile	missense_variant	10/25	1	NM_007315.4	ENSP00000354394.4		P42224-1

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

367

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00776

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00332

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00237

AC:

597

AN:

251406

Hom.:

AF XY:

0.00234

AC XY:

318

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00684

Gnomad NFE exome

AF:

0.00337

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00322

AC:

4705

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00315

AC XY:

2292

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000672

Gnomad4 FIN exome

AF:

0.00639

Gnomad4 NFE exome

AF:

0.00367

Gnomad4 OTH exome

AF:

0.00243

GnomAD4 genome

AF:

0.00241

AC:

367

AN:

152142

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000892

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00776

Gnomad4 NFE

AF:

0.00332

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00270

Hom.:

Bravo

AF:

0.00190

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00204

AC:

248

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	STAT1: PP2, BP4, BS3:Supporting, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 19, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Pathogenic:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 04, 2018	- -

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

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	STAT1 NM_007315.3 exon 10 p.Val266Ile (c.796G>A): This variant has been reported in the literature as a heterozygous variant in at least 8 individuals with varying [inconsistent?] immunodeficiency phenotypes (Uzel 2013 PMID:23534974, Mork 2015 PMID:26513235, Remaschi 2015 PMID:26162368, Szymanski 2015 PMID:26038974, Depner 2016 PMID:26604104, Rae 2018 PMID:29077208). This variant is present in 0.6% (175/25748) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/2-191859935-C-T) and is present in ClinVar with conflicting interpretations ranging from likely benign to pathogenic (Variation ID:333285). Functional studies are also conflicting; one study using flow cytometric anaylsis showed a significant increase in STAT1 phosphorylation with this variant compared to the wildtype, which is consistent with a gain of function effect (Uzel 2013 PMID:23534974). However, a second study using similar methodology showed no evidence for hyperphosphorylation of STAT1 with this variant (Depner 2016 PMID:26604104). This variant amino acid Isoleucine (Ile) is present in several species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

STAT1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Immunodeficiency 31B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Uncertain

0.58

D;D;.;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.88

.;D;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.33

N;N;N;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.39

N;N;N;N

REVEL

Benign

0.29

Sift

Benign

0.69

T;T;T;T

Sift4G

Benign

0.68

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.48

MVP

0.86

MPC

1.1

ClinPred

0.0014

GERP RS

0.79

Varity_R

0.038

gMVP

0.73

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

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