chr17-42201524-G-GCA

Variant names:

• chr17-42201524-G-GCA
• rs57573850
• NM_012448.4:c.*212_*213dupTG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_012448.4(STAT5B):​c.*212_*213dupTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.075 in 610,972 control chromosomes in the GnomAD database, including 435 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.075 (419 hom., cov: 21)
  • Exomes 𝑓: 0.075 (16 hom.)
• Consequence: STAT5B NM_012448.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.111
• Publications: 0 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0817 is higher than 0.05.

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.*212_*213dupTG		3_prime_UTR	Exon 19 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.*212_*213dupTG		3_prime_UTR	Exon 19 of 19	ENSP00000293328.3	P51692
	STAT5B	ENST00000951702.1		c.*212_*213dupTG		3_prime_UTR	Exon 20 of 20	ENSP00000621761.1
	STAT5B	ENST00000415845.2	TSL:4	c.*212_*213dupTG		3_prime_UTR	Exon 19 of 19	ENSP00000398379.2	P51692

Frequencies

GnomAD3 genomes AF: 0.0745 AC: 10846 AN: 145634 Hom.: 419 Cov.: 21

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.0642

Gnomad ASJ AF: 0.0674

Gnomad EAS AF: 0.0605

Gnomad SAS AF: 0.0627

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0789

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.0858

GnomAD4 exome AF: 0.0752 AC: 34975 AN: 465246 Hom.: 16 Cov.: 0 AF XY: 0.0742 AC XY: 18193 AN XY: 245192

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0566 AC: 783 AN: 13822

American (AMR) AF: 0.0555 AC: 1524 AN: 27442

Ashkenazi Jewish (ASJ) AF: 0.0690 AC: 1057 AN: 15316

East Asian (EAS) AF: 0.0435 AC: 1340 AN: 30776

South Asian (SAS) AF: 0.0683 AC: 3304 AN: 48404

European-Finnish (FIN) AF: 0.0984 AC: 3009 AN: 30566

Middle Eastern (MID) AF: 0.0742 AC: 154 AN: 2076

European-Non Finnish (NFE) AF: 0.0802 AC: 21672 AN: 270178

Other (OTH) AF: 0.0800 AC: 2132 AN: 26666

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0745 AC: 10859 AN: 145726 Hom.: 419 Cov.: 21 AF XY: 0.0752 AC XY: 5321 AN XY: 70784

African (AFR) AF: 0.0558 AC: 2245 AN: 40236

American (AMR) AF: 0.0641 AC: 923 AN: 14408

Ashkenazi Jewish (ASJ) AF: 0.0674 AC: 225 AN: 3338

East Asian (EAS) AF: 0.0607 AC: 297 AN: 4894

South Asian (SAS) AF: 0.0624 AC: 282 AN: 4516

European-Finnish (FIN) AF: 0.107 AC: 1026 AN: 9556

Middle Eastern (MID) AF: 0.0857 AC: 24 AN: 280

European-Non Finnish (NFE) AF: 0.0836 AC: 5487 AN: 65642

Other (OTH) AF: 0.0861 AC: 169 AN: 1962

Alfa AF: 0.0290 Hom.: 15

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs57573850; hg19: chr17-40353542;