rs59491077

Variant names:

• chr17-42218327-C-T
• rs59491077
• NM_012448.4:c.993G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-42218327-C-T
• chr17-42218327-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012448.4(STAT5B):​c.993G>A​(p.Thr331Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,612,892 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 30)
  • Exomes 𝑓: 0.0014 (49 hom.)
• Consequence: STAT5B NM_012448.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.800
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-42218327-C-T is Benign according to our data. Variant chr17-42218327-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 199128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (2108/151494) while in subpopulation AFR AF = 0.0491 (2022/41216). AF 95% confidence interval is 0.0473. There are 43 homozygotes in GnomAd4. There are 984 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 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.993G>A	p.Thr331Thr	synonymous	Exon 9 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.993G>A	p.Thr331Thr	synonymous	Exon 9 of 19	ENSP00000293328.3	P51692
	STAT5B	ENST00000468312.1	TSL:1	n.1162G>A		non_coding_transcript_exon	Exon 9 of 9
	STAT5B	ENST00000951702.1		c.993G>A	p.Thr331Thr	synonymous	Exon 9 of 20	ENSP00000621761.1

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2106 AN: 151376 Hom.: 43 Cov.: 30

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00349

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00964

GnomAD2 exomes AF: 0.00366 AC: 920 AN: 251352 AF XY: 0.00278

Gnomad AFR exome AF: 0.0497

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00142 AC: 2075 AN: 1461398 Hom.: 49 Cov.: 32 AF XY: 0.00121 AC XY: 877 AN XY: 726930

African (AFR) AF: 0.0500 AC: 1674 AN: 33478

American (AMR) AF: 0.00259 AC: 116 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39674

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1111602

Other (OTH) AF: 0.00315 AC: 190 AN: 60380

GnomAD4 genome AF: 0.0139 AC: 2108 AN: 151494 Hom.: 43 Cov.: 30 AF XY: 0.0133 AC XY: 984 AN XY: 73966

African (AFR) AF: 0.0491 AC: 2022 AN: 41216

American (AMR) AF: 0.00349 AC: 53 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67950

Other (OTH) AF: 0.00954 AC: 20 AN: 2096

Alfa AF: 0.00464 Hom.: 6

Bravo AF: 0.0157

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Growth hormone insensitivity with immune dysregulation 1, autosomal recessive (1)
-	-	1	Growth hormone insensitivity with immune dysregulation 1, autosomal recessive;C5436546:Growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.25
DANN	Benign	0.58
PhyloP100		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=97/3	polymorphism

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: rs59491077; hg19: chr17-40370345;