chr17-42219455-G-A

Variant names:

• chr17-42219455-G-A
• rs555155085
• NM_012448.4:c.690C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_012448.4(STAT5B):​c.690C>T​(p.Ala230Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,437,330 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 28)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: STAT5B NM_012448.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.45
• 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: 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 17-42219455-G-A is Benign according to our data. Variant chr17-42219455-G-A is described in ClinVar as Benign. ClinVar VariationId is 466225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00241 (349/144518) while in subpopulation AFR AF = 0.00859 (333/38766). AF 95% confidence interval is 0.00783. There are 1 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT5B	NM_012448.4	MANE Select	c.690C>T	p.Ala230Ala	synonymous	Exon 7 of 19	NP_036580.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAT5B	ENST00000293328.8	TSL:1 MANE Select	c.690C>T	p.Ala230Ala	synonymous	Exon 7 of 19	ENSP00000293328.3
	STAT5B	ENST00000468312.1	TSL:1	n.859C>T		non_coding_transcript_exon	Exon 7 of 9
	STAT5B	ENST00000415845.2	TSL:4	c.690C>T	p.Ala230Ala	synonymous	Exon 7 of 19	ENSP00000398379.2

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 349 AN: 144412 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000551

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000456

Gnomad OTH AF: 0.00259

GnomAD2 exomes AF: 0.000816 AC: 71 AN: 87048 AF XY: 0.000744

Gnomad AFR exome AF: 0.00995

Gnomad AMR exome AF: 0.000382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000323

Gnomad OTH exome AF: 0.000362

GnomAD4 exome AF: 0.000338 AC: 437 AN: 1292812 Hom.: 4 Cov.: 22 AF XY: 0.000279 AC XY: 178 AN XY: 636914

African (AFR) AF: 0.0123 AC: 367 AN: 29758

American (AMR) AF: 0.000355 AC: 12 AN: 33768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22702

East Asian (EAS) AF: 0.00 AC: 0 AN: 35240

South Asian (SAS) AF: 0.0000677 AC: 5 AN: 73820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39894

Middle Eastern (MID) AF: 0.000263 AC: 1 AN: 3806

European-Non Finnish (NFE) AF: 0.0000160 AC: 16 AN: 999628

Other (OTH) AF: 0.000664 AC: 36 AN: 54196

GnomAD4 genome AF: 0.00241 AC: 349 AN: 144518 Hom.: 1 Cov.: 28 AF XY: 0.00223 AC XY: 156 AN XY: 69972

African (AFR) AF: 0.00859 AC: 333 AN: 38766

American (AMR) AF: 0.000550 AC: 8 AN: 14544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3406

East Asian (EAS) AF: 0.00 AC: 0 AN: 4918

South Asian (SAS) AF: 0.00 AC: 0 AN: 4208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000456 AC: 3 AN: 65720

Other (OTH) AF: 0.00256 AC: 5 AN: 1954

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00303

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Growth hormone insensitivity with immune dysregulation 1, autosomal recessive Benign:1

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.7
DANN	Benign	0.70
PhyloP100		-2.4
Mutation Taster		=99/1	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: rs555155085; hg19: chr17-40371473;