17-42201524-GCACACACACACACACACACACACA-GCACACACACACACACACACACA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_012448.4(STAT5B):​c.*212_*213delTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 435,538 control chromosomes in the GnomAD database, including 1,507 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.10 (1480 hom., cov: 21)
  • Exomes 𝑓: 0.23 (27 hom.)
• Consequence: STAT5B NM_012448.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 17-42201524-GCA-G is Benign according to our data. Variant chr17-42201524-GCA-G is described in ClinVar as Benign. ClinVar VariationId is 1244365.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.262 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_*213delTG		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_*213delTG		3_prime_UTR	Exon 19 of 19	ENSP00000293328.3	P51692
	STAT5B	ENST00000951702.1		c.*212_*213delTG		3_prime_UTR	Exon 20 of 20	ENSP00000621761.1
	STAT5B	ENST00000415845.2	TSL:4	c.*212_*213delTG		3_prime_UTR	Exon 19 of 19	ENSP00000398379.2	P51692

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15033 AN: 145088 Hom.: 1472 Cov.: 21

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.0804

Gnomad AMR AF: 0.0577

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.0374

Gnomad SAS AF: 0.0619

Gnomad FIN AF: 0.0287

Gnomad MID AF: 0.0464

Gnomad NFE AF: 0.0377

Gnomad OTH AF: 0.0799

GnomAD4 exome AF: 0.231 AC: 67118 AN: 290364 Hom.: 27 AF XY: 0.234 AC XY: 36034 AN XY: 154318

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

African (AFR) AF: 0.319 AC: 3693 AN: 11560

American (AMR) AF: 0.267 AC: 5168 AN: 19356

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 2148 AN: 8504

East Asian (EAS) AF: 0.241 AC: 3813 AN: 15796

South Asian (SAS) AF: 0.279 AC: 10220 AN: 36660

European-Finnish (FIN) AF: 0.152 AC: 2882 AN: 18966

Middle Eastern (MID) AF: 0.262 AC: 316 AN: 1208

European-Non Finnish (NFE) AF: 0.217 AC: 35110 AN: 161952

Other (OTH) AF: 0.230 AC: 3768 AN: 16362

⚠️ 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: 0.104 AC: 15077 AN: 145174 Hom.: 1480 Cov.: 21 AF XY: 0.104 AC XY: 7318 AN XY: 70482

African (AFR) AF: 0.267 AC: 10711 AN: 40168

American (AMR) AF: 0.0578 AC: 828 AN: 14336

Ashkenazi Jewish (ASJ) AF: 0.0288 AC: 96 AN: 3336

East Asian (EAS) AF: 0.0377 AC: 184 AN: 4884

South Asian (SAS) AF: 0.0623 AC: 281 AN: 4512

European-Finnish (FIN) AF: 0.0287 AC: 269 AN: 9368

Middle Eastern (MID) AF: 0.0504 AC: 14 AN: 278

European-Non Finnish (NFE) AF: 0.0377 AC: 2467 AN: 65442

Other (OTH) AF: 0.0793 AC: 155 AN: 1954

Alfa AF: 0.0201 Hom.: 15

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs57573850; hg19: chr17-40353542; COSMIC: COSV53186083; COSMIC: COSV53186083;