chr17-42300766-G-C

Position:

• chr17-42300766-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001288718.2(STAT5A):​c.885G>C​(p.Arg295Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STAT5A NM_001288718.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.927

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT5A	NM_001288718.2	c.885G>C	p.Arg295Ser	missense_variant	8/19	ENST00000590949.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT5A	ENST00000590949.6	c.885G>C	p.Arg295Ser	missense_variant	8/19	1	NM_001288718.2	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461048 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

The c.885G>C (p.R295S) alteration is located in exon 9 (coding exon 7) of the STAT5A gene. This alteration results from a G to C substitution at nucleotide position 885, causing the arginine (R) at amino acid position 295 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;D;.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.073	N
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.0	N;.;N;.
REVEL	Benign	0.28
Sift	Benign	0.088	T;.;T;.
Sift4G	Benign	0.65	T;T;T;T
Polyphen		0.22	B;B;.;.
Vest4		0.81
MutPred		0.62		Loss of MoRF binding (P = 0.0326);Loss of MoRF binding (P = 0.0326);.;Loss of MoRF binding (P = 0.0326);
MVP		0.93
MPC		2.6
ClinPred		0.59	D
GERP RS		-1.2
Varity_R		0.30
gMVP		0.65

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: rs919902354; hg19: chr17-40452784;