NM_012448.4:c.376-307C>A

Variant names:

• chr17-42223863-G-T
• rs9900213
• NM_012448.4:c.376-307C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012448.4(STAT5B):​c.376-307C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 151,992 control chromosomes in the GnomAD database, including 8,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.28 (8399 hom., cov: 31)
• Consequence: STAT5B NM_012448.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.48
• Publications: 31 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: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• growth hormone insensitivity syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-42223863-G-T is Benign according to our data. Variant chr17-42223863-G-T is described in ClinVar as Benign. ClinVar VariationId is 1220855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.551 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT5B	NM_012448.4	MANE Select	c.376-307C>A		intron	N/A	NP_036580.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT5B	ENST00000293328.8	TSL:1 MANE Select	c.376-307C>A		intron	N/A	ENSP00000293328.3
	STAT5B	ENST00000468312.1	TSL:1	n.545-307C>A		intron	N/A
	STAT5B	ENST00000698804.1		n.1410C>A		non_coding_transcript_exon	Exon 4 of 16

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42464 AN: 151872 Hom.: 8361 Cov.: 31

Gnomad AFR AF: 0.557

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.227

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.280 AC: 42561 AN: 151992 Hom.: 8399 Cov.: 31 AF XY: 0.278 AC XY: 20664 AN XY: 74294

African (AFR) AF: 0.557 AC: 23102 AN: 41446

American (AMR) AF: 0.135 AC: 2058 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 457 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1527 AN: 5168

South Asian (SAS) AF: 0.302 AC: 1454 AN: 4810

European-Finnish (FIN) AF: 0.191 AC: 2014 AN: 10558

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11327 AN: 67964

Other (OTH) AF: 0.229 AC: 482 AN: 2106

Alfa AF: 0.194 Hom.: 15441

Bravo AF: 0.285

Asia WGS AF: 0.371 AC: 1288 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.10
DANN	Benign	0.32
PhyloP100		-1.5
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: rs9900213; hg19: chr17-40375881;