rs750095303

chr17-42202416-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS1_Supporting

The NM_012448.4(STAT5B):c.2161G>A(p.Gly721Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,614,216 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (1 hom.)
• Consequence: STAT5B NM_012448.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.879

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, STAT5B
• BP4: Computational evidence support a benign effect (MetaRNN=0.069301635).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000093 (136/1461862) while in subpopulation MID AF= 0.00677 (39/5758). AF 95% confidence interval is 0.00509. There are 1 homozygotes in gnomad4_exome. There are 65 alleles in male gnomad4_exome subpopulation. Median coverage is 32. 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
STAT5B	NM_012448.4	c.2161G>A	p.Gly721Ser	missense_variant	18/19	ENST00000293328.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT5B	ENST00000293328.8	c.2161G>A	p.Gly721Ser	missense_variant	18/19	1	NM_012448.4	P4

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152236 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251268 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000930 AC: 136 AN: 1461862 Hom.: 1 Cov.: 32 AF XY: 0.0000894 AC XY: 65 AN XY: 727228

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000665

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152354 Hom.: 1 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74506

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Growth hormone insensitivity with immune dysregulation 1, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 721 of the STAT5B protein (p.Gly721Ser). This variant is present in population databases (rs750095303, gnomAD 0.01%). 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: 572813). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 20, 2023

Variant summary: STAT5B c.2161G>A (p.Gly721Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251268 control chromosomes. To our knowledge, no occurrence of c.2161G>A in individuals affected with Growth Hormone Insensitivity Syndrome With Immune Dysregulation 2, Autosomal Dominant and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	5.5
Dann	Benign	0.55
DEOGEN2	Benign	0.079	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.14
Sift	Benign	0.35	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.53
MPC		1.1
ClinPred		0.016	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.021
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs750095303; hg19: chr17-40354434; COSMIC: COSV53183873;