17-42201524-GCACACACACACACACACACACACA-GCACACACACACACACACACACACACACACA

Variant names:

• chr17-42201524-G-GCACACA
• rs57573850
• NM_012448.4:c.*208_*213dupTGTGTG

Variant summary

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

The NM_012448.4(STAT5B):​c.*208_*213dupTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 617,396 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 0.00049 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00032 (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 afr. GnomAd4 allele frequency = 0.000494 (72/145830) while in subpopulation AFR AF = 0.00117 (47/40252). AF 95% confidence interval is 0.000901. There are 0 homozygotes in GnomAd4. There are 39 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.*208_*213dupTGTGTG		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.*208_*213dupTGTGTG		3_prime_UTR	Exon 19 of 19	ENSP00000293328.3	P51692
	STAT5B	ENST00000951702.1		c.*208_*213dupTGTGTG		3_prime_UTR	Exon 20 of 20	ENSP00000621761.1
	STAT5B	ENST00000415845.2	TSL:4	c.*208_*213dupTGTGTG		3_prime_UTR	Exon 19 of 19	ENSP00000398379.2	P51692

Frequencies

GnomAD3 genomes AF: 0.000494 AC: 72 AN: 145740 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000139

Gnomad ASJ AF: 0.000300

Gnomad EAS AF: 0.000407

Gnomad SAS AF: 0.000221

Gnomad FIN AF: 0.000209

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000244

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000316 AC: 149 AN: 471566 Hom.: 0 Cov.: 0 AF XY: 0.000294 AC XY: 73 AN XY: 248624

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

African (AFR) AF: 0.00122 AC: 17 AN: 13910

American (AMR) AF: 0.000357 AC: 10 AN: 28028

Ashkenazi Jewish (ASJ) AF: 0.000773 AC: 12 AN: 15526

East Asian (EAS) AF: 0.0000966 AC: 3 AN: 31060

South Asian (SAS) AF: 0.000161 AC: 8 AN: 49582

European-Finnish (FIN) AF: 0.000195 AC: 6 AN: 30836

Middle Eastern (MID) AF: 0.00238 AC: 5 AN: 2098

European-Non Finnish (NFE) AF: 0.000274 AC: 75 AN: 273554

Other (OTH) AF: 0.000482 AC: 13 AN: 26972

⚠️ 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: 0.000494 AC: 72 AN: 145830 Hom.: 0 Cov.: 21 AF XY: 0.000551 AC XY: 39 AN XY: 70840

African (AFR) AF: 0.00117 AC: 47 AN: 40252

American (AMR) AF: 0.000139 AC: 2 AN: 14424

Ashkenazi Jewish (ASJ) AF: 0.000300 AC: 1 AN: 3338

East Asian (EAS) AF: 0.000408 AC: 2 AN: 4898

South Asian (SAS) AF: 0.000221 AC: 1 AN: 4516

European-Finnish (FIN) AF: 0.000209 AC: 2 AN: 9580

Middle Eastern (MID) AF: 0.00357 AC: 1 AN: 280

European-Non Finnish (NFE) AF: 0.000244 AC: 16 AN: 65682

Other (OTH) AF: 0.00 AC: 0 AN: 1964

Alfa AF: 0.00 Hom.: 15

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11

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;