17-42201524-GCACACACACACACACACACACACA-GCACACACACACACACACA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_012448.4(STAT5B):​c.*208_*213delTGTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 615,590 control chromosomes in the GnomAD database, including 23 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 21)
  • Exomes 𝑓: 0.0025 (1 hom.)
• Consequence: STAT5B NM_012448.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• 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.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1468/145816) while in subpopulation AFR AF = 0.0332 (1336/40244). AF 95% confidence interval is 0.0317. There are 22 homozygotes in GnomAd4. There are 679 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,SD,AD gene

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_*213delTGTGTG		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_*213delTGTGTG		3_prime_UTR	Exon 19 of 19	ENSP00000293328.3	P51692
	STAT5B	ENST00000951702.1		c.*208_*213delTGTGTG		3_prime_UTR	Exon 20 of 20	ENSP00000621761.1
	STAT5B	ENST00000415845.2	TSL:4	c.*208_*213delTGTGTG		3_prime_UTR	Exon 19 of 19	ENSP00000398379.2	P51692

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1464 AN: 145726 Hom.: 22 Cov.: 21

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00333

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00204

Gnomad SAS AF: 0.000663

Gnomad FIN AF: 0.000313

Gnomad MID AF: 0.00658

Gnomad NFE AF: 0.000731

Gnomad OTH AF: 0.00924

GnomAD4 exome AF: 0.00252 AC: 1186 AN: 469774 Hom.: 1 AF XY: 0.00238 AC XY: 590 AN XY: 247746

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

African (AFR) AF: 0.0366 AC: 506 AN: 13836

American (AMR) AF: 0.00200 AC: 56 AN: 27998

Ashkenazi Jewish (ASJ) AF: 0.000451 AC: 7 AN: 15508

East Asian (EAS) AF: 0.00103 AC: 32 AN: 30950

South Asian (SAS) AF: 0.00172 AC: 85 AN: 49482

European-Finnish (FIN) AF: 0.00157 AC: 48 AN: 30536

Middle Eastern (MID) AF: 0.00239 AC: 5 AN: 2096

European-Non Finnish (NFE) AF: 0.00127 AC: 345 AN: 272480

Other (OTH) AF: 0.00379 AC: 102 AN: 26888

⚠️ 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: 0.0101 AC: 1468 AN: 145816 Hom.: 22 Cov.: 21 AF XY: 0.00959 AC XY: 679 AN XY: 70836

African (AFR) AF: 0.0332 AC: 1336 AN: 40244

American (AMR) AF: 0.00333 AC: 48 AN: 14422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3338

East Asian (EAS) AF: 0.00204 AC: 10 AN: 4898

South Asian (SAS) AF: 0.000664 AC: 3 AN: 4516

European-Finnish (FIN) AF: 0.000313 AC: 3 AN: 9576

Middle Eastern (MID) AF: 0.00714 AC: 2 AN: 280

European-Non Finnish (NFE) AF: 0.000731 AC: 48 AN: 65682

Other (OTH) AF: 0.00916 AC: 18 AN: 1964

Alfa AF: 0.000377 Hom.: 15

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
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;