rs372508550

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_007315.4(STAT1):​c.1127+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,610,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

STAT1
NM_007315.4 splice_donor_region, intron

Scores

2
Splicing: ADA: 0.00005063
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -3.92
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000117 (171/1458038) while in subpopulation AFR AF= 0.00018 (6/33378). AF 95% confidence interval is 0.000127. There are 0 homozygotes in gnomad4_exome. There are 66 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
STAT1NM_007315.4 linkuse as main transcriptc.1127+4C>T splice_donor_region_variant, intron_variant ENST00000361099.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STAT1ENST00000361099.8 linkuse as main transcriptc.1127+4C>T splice_donor_region_variant, intron_variant 1 NM_007315.4 P4P42224-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152052
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000967
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000399
AC:
10
AN:
250918
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135696
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000617
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000117
AC:
171
AN:
1458038
Hom.:
0
Cov.:
30
AF XY:
0.0000910
AC XY:
66
AN XY:
725626
show subpopulations
Gnomad4 AFR exome
AF:
0.000180
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000145
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152052
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.0000967
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000580
Hom.:
0
Bravo
AF:
0.0000642
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 22, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 474980). This variant has not been reported in the literature in individuals affected with STAT1-related conditions. This variant is present in population databases (rs372508550, gnomAD 0.02%). This sequence change falls in intron 13 of the STAT1 gene. It does not directly change the encoded amino acid sequence of the STAT1 protein. It affects a nucleotide within the consensus splice site. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
0.018
DANN
Benign
0.72
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000051
dbscSNV1_RF
Benign
0.016
SpliceAI score (max)
0.10
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.

Other links and lift over

dbSNP: rs372508550; hg19: chr2-191851761; COSMIC: COSV63117775; COSMIC: COSV63117775; API