17-42201830-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_012448.4(STAT5B):​c.2272G>A​(p.Asp758Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

STAT5B
NM_012448.4 missense

Scores

5
6
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.74
Variant links:
Genes affected
STAT5B (HGNC:11367): (signal transducer and activator of transcription 5B) The protein encoded by this gene is a member of the STAT family of transcription factors. 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. This protein mediates the signal transduction triggered by various cell ligands, such as IL2, IL4, CSF1, and different growth hormones. It has been shown to be involved in diverse biological processes, such as TCR signaling, apoptosis, adult mammary gland development, and sexual dimorphism of liver gene expression. This gene was found to fuse to retinoic acid receptor-alpha (RARA) gene in a small subset of acute promyelocytic leukemias (APLL). The dysregulation of the signaling pathways mediated by this protein may be the cause of the APLL. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAT5B. . Gene score misZ 3.9952 (greater than the threshold 3.09). Trascript score misZ 5.1164 (greater than threshold 3.09). GenCC has associacion of gene with growth hormone insensitivity syndrome with immune dysregulation, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
STAT5BNM_012448.4 linkuse as main transcriptc.2272G>A p.Asp758Asn missense_variant 19/19 ENST00000293328.8 NP_036580.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
STAT5BENST00000293328.8 linkuse as main transcriptc.2272G>A p.Asp758Asn missense_variant 19/191 NM_012448.4 ENSP00000293328 P4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461768
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727180
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Growth hormone insensitivity with immune dysregulation 1, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 13, 2023This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 758 of the STAT5B protein (p.Asp758Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STAT5B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1017370). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.0011
T
BayesDel_noAF
Benign
-0.24
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.21
T
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.33
D
MetaRNN
Uncertain
0.47
T
MetaSVM
Uncertain
0.68
D
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.7
N
REVEL
Uncertain
0.45
Sift
Uncertain
0.010
D
Sift4G
Benign
0.12
T
Polyphen
1.0
D
Vest4
0.40
MutPred
0.23
Gain of loop (P = 0.0851);
MVP
0.92
MPC
2.1
ClinPred
0.99
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.20
gMVP
0.58

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.

Other links and lift over

dbSNP: rs1489641088; hg19: chr17-40353848; API