chr2-190977033-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007315.4(STAT1):c.1874-8C>T variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.00003493

Clinical Significance

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

Conservation

PhyloP100: -0.225

Publications

41 publications found

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 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)

STAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 333264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
STAT1	NM_007315.4 link	c.1874-8C>T		splice_region_variant, intron_variant	Intron 21 of 24	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8 link	c.1874-8C>T		splice_region_variant, intron_variant	Intron 21 of 24	1	NM_007315.4	ENSP00000354394.4

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

GnomAD2 exomes

AF:

0.226

AC:

56832

AN:

250966

AF XY:

0.229

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 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

African (AFR)

AF:

0.171

AC:

5733

AN:

33472

American (AMR)

AF:

0.117

AC:

5250

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.245

AC:

6409

AN:

26124

East Asian (EAS)

AF:

0.487

AC:

19323

AN:

39690

South Asian (SAS)

AF:

0.176

AC:

15216

AN:

86244

European-Finnish (FIN)

AF:

0.236

AC:

12609

AN:

53394

Middle Eastern (MID)

AF:

0.213

AC:

1230

AN:

5764

European-Non Finnish (NFE)

AF:

0.255

AC:

283746

AN:

1111306

Other (OTH)

AF:

0.242

AC:

14613

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

13501

27002

40503

54004

67505

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9688

19376

29064

38752

48440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.222

AC:

33767

AN:

151940

Hom.:

4048

Cov.:

AF XY:

0.220

AC XY:

16341

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.171

AC:

7088

AN:

41434

American (AMR)

AF:

0.170

AC:

2589

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.258

AC:

895

AN:

3468

East Asian (EAS)

AF:

0.450

AC:

2328

AN:

5172

South Asian (SAS)

AF:

0.183

AC:

877

AN:

4804

European-Finnish (FIN)

AF:

0.244

AC:

2578

AN:

10552

Middle Eastern (MID)

AF:

0.193

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.245

AC:

16663

AN:

67944

Other (OTH)

AF:

0.213

AC:

450

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1330

2661

3991

5322

6652

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.234

Hom.:

6938

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.46

PhyloP100

-0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over