17-42201524-GCACACACACACACACACACACACA-GCACACACACACACACACACACACACACA

Variant names:

• chr17-42201524-G-GCACA
• rs57573850
• NM_012448.4:c.*210_*213dupTGTG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_012448.4(STAT5B):​c.*210_*213dupTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 617,200 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0044 (0 hom., cov: 21)
  • Exomes 𝑓: 0.0044 (0 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00441 (643/145820) while in subpopulation AMR AF = 0.0068 (98/14422). AF 95% confidence interval is 0.00571. There are 0 homozygotes in GnomAd4. There are 293 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

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.*210_*213dupTGTG		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.*210_*213dupTGTG		3_prime_UTR	Exon 19 of 19	ENSP00000293328.3	P51692
	STAT5B	ENST00000951702.1		c.*210_*213dupTGTG		3_prime_UTR	Exon 20 of 20	ENSP00000621761.1
	STAT5B	ENST00000415845.2	TSL:4	c.*210_*213dupTGTG		3_prime_UTR	Exon 19 of 19	ENSP00000398379.2	P51692

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 641 AN: 145730 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00680

Gnomad ASJ AF: 0.00240

Gnomad EAS AF: 0.00163

Gnomad SAS AF: 0.00487

Gnomad FIN AF: 0.00251

Gnomad MID AF: 0.0197

Gnomad NFE AF: 0.00489

Gnomad OTH AF: 0.00513

GnomAD4 exome AF: 0.00444 AC: 2094 AN: 471380 Hom.: 0 Cov.: 0 AF XY: 0.00451 AC XY: 1120 AN XY: 248512

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

African (AFR) AF: 0.00532 AC: 74 AN: 13906

American (AMR) AF: 0.00428 AC: 120 AN: 28012

Ashkenazi Jewish (ASJ) AF: 0.000709 AC: 11 AN: 15518

East Asian (EAS) AF: 0.00119 AC: 37 AN: 31058

South Asian (SAS) AF: 0.00553 AC: 274 AN: 49540

European-Finnish (FIN) AF: 0.00240 AC: 74 AN: 30824

Middle Eastern (MID) AF: 0.00810 AC: 17 AN: 2098

European-Non Finnish (NFE) AF: 0.00497 AC: 1360 AN: 273464

Other (OTH) AF: 0.00471 AC: 127 AN: 26960

⚠️ 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: 0.00441 AC: 643 AN: 145820 Hom.: 0 Cov.: 21 AF XY: 0.00414 AC XY: 293 AN XY: 70834

African (AFR) AF: 0.00360 AC: 145 AN: 40250

American (AMR) AF: 0.00680 AC: 98 AN: 14422

Ashkenazi Jewish (ASJ) AF: 0.00240 AC: 8 AN: 3338

East Asian (EAS) AF: 0.00163 AC: 8 AN: 4898

South Asian (SAS) AF: 0.00510 AC: 23 AN: 4512

European-Finnish (FIN) AF: 0.00251 AC: 24 AN: 9580

Middle Eastern (MID) AF: 0.0214 AC: 6 AN: 280

European-Non Finnish (NFE) AF: 0.00489 AC: 321 AN: 65680

Other (OTH) AF: 0.00509 AC: 10 AN: 1964

Alfa AF: 0.00166 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

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;