rs7218653

Variant names:

• chr17-42273302-A-G
• rs7218653
• NM_012448.4:c.-11+2946T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012448.4(STAT5B):​c.-11+2946T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 152,036 control chromosomes in the GnomAD database, including 10,827 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10827 hom., cov: 32)
• Consequence: STAT5B NM_012448.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.509
• Publications: 16 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

ENSG00000278829 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT5B	NM_012448.4	c.-11+2946T>C		intron_variant	Intron 1 of 18	ENST00000293328.8	NP_036580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT5B	ENST00000293328.8	c.-11+2946T>C		intron_variant	Intron 1 of 18	1	NM_012448.4	ENSP00000293328.3

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54130 AN: 151918 Hom.: 10810 Cov.: 32

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.356

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

GnomAD4 genome AF: 0.356 AC: 54196 AN: 152036 Hom.: 10827 Cov.: 32 AF XY: 0.353 AC XY: 26261 AN XY: 74334

African (AFR) AF: 0.540 AC: 22378 AN: 41432

American (AMR) AF: 0.212 AC: 3235 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1169 AN: 3472

East Asian (EAS) AF: 0.357 AC: 1853 AN: 5188

South Asian (SAS) AF: 0.424 AC: 2043 AN: 4822

European-Finnish (FIN) AF: 0.237 AC: 2502 AN: 10570

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.294 AC: 19975 AN: 67962

Other (OTH) AF: 0.357 AC: 753 AN: 2110

Alfa AF: 0.313 Hom.: 1677

Bravo AF: 0.359

Asia WGS AF: 0.435 AC: 1508 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.7
DANN	Benign	0.78
PhyloP100		0.51
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: rs7218653; hg19: chr17-40425320;