chr17-42299763-A-C

Position:

• chr17-42299763-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001288718.2(STAT5A):​c.563A>C​(p.Gln188Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: STAT5A NM_001288718.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.86

Genes affected

STAT5A (HGNC:11366): (signal transducer and activator of transcription 5A) 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 is activated by, and mediates the responses of many cell ligands, such as IL2, IL3, IL7 GM-CSF, erythropoietin, thrombopoietin, and different growth hormones. Activation of this protein in myeloma and lymphoma associated with a TEL/JAK2 gene fusion is independent of cell stimulus and has been shown to be essential for tumorigenesis. The mouse counterpart of this gene is found to induce the expression of BCL2L1/BCL-X(L), which suggests the antiapoptotic function of this gene in cells. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11686447).
• BP6: Variant 17-42299763-A-C is Benign according to our data. Variant chr17-42299763-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2455504.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT5A	NM_001288718.2	c.563A>C	p.Gln188Pro	missense_variant	6/19	ENST00000590949.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT5A	ENST00000590949.6	c.563A>C	p.Gln188Pro	missense_variant	6/19	1	NM_001288718.2	P4

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152188 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251386 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135886

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 171 AN: 1461818 Hom.: 0 Cov.: 32 AF XY: 0.000117 AC XY: 85 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152306 Hom.: 0 Cov.: 28 AF XY: 0.0000806 AC XY: 6 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000180 Hom.: 0

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	4.8
DANN	Benign	0.81
DEOGEN2	Pathogenic	0.81	D;D;.;D;D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.55	.;T;T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.5	M;M;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.4	N;.;N;.;.
REVEL	Benign	0.21
Sift	Benign	0.19	T;.;T;.;.
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.35
MVP		0.48
MPC		0.59
ClinPred		0.061	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs576311406; hg19: chr17-40451781; COSMIC: COSV100604576; COSMIC: COSV100604576;