2-190987072-CA-CAA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS1

The NM_007315.4(STAT1):c.1098-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000337 in 1,596,784 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

STAT1
NM_007315.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.27

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 2-190987072-C-CA is Benign according to our data. Variant chr2-190987072-C-CA is described in ClinVar as Benign. ClinVar VariationId is 541831.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00137 (207/151524) while in subpopulation AFR AF = 0.00445 (184/41348). AF 95% confidence interval is 0.00392. There are 0 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007315.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
STAT1	NM_007315.4	MANE Select	c.1098-5dupT	splice_region intron	N/A	NP_009330.1
STAT1	NM_001384891.1		c.1134-5dupT	splice_region intron	N/A	NP_001371820.1
STAT1	NM_001384886.1		c.1098-5dupT	splice_region intron	N/A	NP_001371815.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
STAT1	ENST00000361099.8	TSL:1 MANE Select	c.1098-5_1098-4insT	splice_region intron	N/A	ENSP00000354394.4
STAT1	ENST00000409465.5	TSL:1	c.1098-5_1098-4insT	splice_region intron	N/A	ENSP00000386244.1
STAT1	ENST00000392322.7	TSL:1	c.1098-5_1098-4insT	splice_region intron	N/A	ENSP00000376136.3

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

207

AN:

151408

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00446

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000460

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.000357

AC:

AN:

243928

AF XY:

0.000257

show subpopulations

Gnomad AFR exome

AF:

0.00416

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000146

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000229

AC:

331

AN:

1445260

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

151

AN XY:

719742

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00406

AC:

134

AN:

33020

American (AMR)

AF:

0.000202

AC:

AN:

44584

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26038

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39556

South Asian (SAS)

AF:

0.0000467

AC:

AN:

85666

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.000218

AC:

AN:

4578

European-Non Finnish (NFE)

AF:

0.000140

AC:

154

AN:

1098780

Other (OTH)

AF:

0.000436

AC:

AN:

59696

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00137

AC:

207

AN:

151524

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

AN XY:

74062

show subpopulations

African (AFR)

AF:

0.00445

AC:

184

AN:

41348

American (AMR)

AF:

0.000459

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67814

Other (OTH)

AF:

0.00285

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000146

Hom.:

Bravo

AF:

0.00159

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency (1)

STAT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over