rs750095303

Variant names:

• chr17-42202416-C-T
• rs750095303
• NM_012448.4:c.2161G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. 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. 17/22 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:6
• Conservation: PhyloP100: 0.879
• Publications: 4 publications found

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: AD, AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• growth hormone insensitivity syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.069301635).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 65 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012448.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT5B	NM_012448.4	MANE Select	c.2161G>A	p.Gly721Ser	missense	Exon 18 of 19	NP_036580.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT5B	ENST00000293328.8	TSL:1 MANE Select	c.2161G>A	p.Gly721Ser	missense	Exon 18 of 19	ENSP00000293328.3	P51692
	STAT5B	ENST00000951702.1		c.2260G>A	p.Gly754Ser	missense	Exon 19 of 20	ENSP00000621761.1
	STAT5B	ENST00000415845.2	TSL:4	c.2161G>A	p.Gly721Ser	missense	Exon 18 of 19	ENSP00000398379.2	P51692

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

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251268 AF XY: 0.0000957

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 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

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00677 AC: 39 AN: 5758

European-Non Finnish (NFE) AF: 0.0000665 AC: 74 AN: 1112000

Other (OTH) AF: 0.000149 AC: 9 AN: 60390

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

African (AFR) AF: 0.0000240 AC: 1 AN: 41590

American (AMR) AF: 0.000327 AC: 5 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Growth hormone insensitivity with immune dysregulation 1, autosomal recessive (1)
-	1	-	Growth hormone insensitivity with immune dysregulation 1, autosomal recessive;C5436546:Growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.88
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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

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