NM_012448.4:c.691G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_012448.4(STAT5B):c.691G>A(p.Glu231Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000024 in 1,294,354 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 0.000014 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000024 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STAT5B
NM_012448.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.67

Publications

1 publications found

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]

STAT5B Gene-Disease associations (from GenCC):

growth hormone insensitivity syndrome with immune dysregulation
Inheritance: SD Classification: DEFINITIVE Submitted by: Illumina
growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
growth hormone insensitivity with immune dysregulation 1, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
growth hormone insensitivity syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

STAT5B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.37456238).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT5B	NM_012448.4 link	c.691G>A	p.Glu231Lys	missense_variant	Exon 7 of 19	ENST00000293328.8	NP_036580.2	P51692

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT5B	ENST00000293328.8 link	c.691G>A	p.Glu231Lys	missense_variant	Exon 7 of 19	1	NM_012448.4	ENSP00000293328.3		P51692

Frequencies

GnomAD3 genomes

AF:

0.0000138

AC:

AN:

144670

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000304

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000345

AC:

AN:

87078

AF XY:

0.0000218

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000164

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1294354

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

637480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29782

American (AMR)

AF:

0.000178

AC:

AN:

33764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22730

East Asian (EAS)

AF:

0.00

AC:

AN:

35252

South Asian (SAS)

AF:

0.0000135

AC:

AN:

73828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3808

European-Non Finnish (NFE)

AF:

0.0000220

AC:

AN:

1001014

Other (OTH)

AF:

0.0000369

AC:

AN:

54246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000138

AC:

AN:

144772

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

70124

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38876

American (AMR)

AF:

0.00

AC:

AN:

14576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

4916

South Asian (SAS)

AF:

0.00

AC:

AN:

4206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000304

AC:

AN:

65808

Other (OTH)

AF:

0.00

AC:

AN:

1952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 231 of the STAT5B protein (p.Glu231Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 534578). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STAT5B protein function with a negative predictive value of 80%. 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

0.14

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Benign

0.11

Eigen_PC

Benign

0.18

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.084

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.4

PhyloP100

4.7

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.30

Sift

Benign

0.11

Sift4G

Benign

0.19

Polyphen

0.23

Vest4

0.40

MutPred

0.51

Gain of MoRF binding (P = 0.003);

MVP

0.91

MPC

3.3

ClinPred

0.25

GERP RS

3.3

Varity_R

0.26

gMVP

0.46

Mutation Taster

=39/61

disease causing

(source)

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over