17-42304551-G-A

Position:

• chr17-42304551-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001288718.2(STAT5A):​c.1279G>A​(p.Ala427Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: STAT5A NM_001288718.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.19

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23317227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT5A	NM_001288718.2	c.1279G>A	p.Ala427Thr	missense_variant	11/19	ENST00000590949.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT5A	ENST00000590949.6	c.1279G>A	p.Ala427Thr	missense_variant	11/19	1	NM_001288718.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Esophageal atresia;C0034194:Pyloric stenosis Uncertain:1

Uncertain significance, no assertion criteria provided

research

Clinical Genetics, Erasmus University Medical Center

May 22, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	.;D;T;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.81	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.8	N;.;N;.
REVEL	Benign	0.27
Sift	Benign	0.14	T;.;T;.
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.0070	B;B;.;.
Vest4		0.24
MutPred		0.56		Gain of phosphorylation at A427 (P = 0.0026);Gain of phosphorylation at A427 (P = 0.0026);.;Gain of phosphorylation at A427 (P = 0.0026);
MVP		0.68
MPC		0.88
ClinPred		0.52	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.056
gMVP		0.12

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: rs1598364148; hg19: chr17-40456569;