17-42299826-T-C

Position:

• chr17-42299826-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001288718.2(STAT5A):​c.626T>C​(p.Val209Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,612,930 control chromosomes in the GnomAD database, including 199 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (93 hom., cov: 28)
  • Exomes 𝑓: 0.0026 (106 hom.)
• Consequence: STAT5A NM_001288718.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.99

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014700294).
• BP6: Variant 17-42299826-T-C is Benign according to our data. Variant chr17-42299826-T-C is described in ClinVar as [Benign]. Clinvar id is 785569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAT5A	NM_001288718.2	c.626T>C	p.Val209Ala	missense_variant	6/19	ENST00000590949.6	NP_001275647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAT5A	ENST00000590949.6	c.626T>C	p.Val209Ala	missense_variant	6/19	1	NM_001288718.2	ENSP00000468749	P4

Frequencies

GnomAD3 genomes AF: 0.0200 AC: 3025 AN: 151370 Hom.: 92 Cov.: 28

Gnomad AFR AF: 0.0688

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00781

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00252

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000457

Gnomad OTH AF: 0.0140

GnomAD3 exomes AF: 0.00601 AC: 1504 AN: 250044 Hom.: 36 AF XY: 0.00478 AC XY: 648 AN XY: 135430

Gnomad AFR exome AF: 0.0730

Gnomad AMR exome AF: 0.00504

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000558

Gnomad OTH exome AF: 0.00639

GnomAD4 exome AF: 0.00255 AC: 3731 AN: 1461442 Hom.: 106 Cov.: 32 AF XY: 0.00232 AC XY: 1690 AN XY: 727026

Gnomad4 AFR exome AF: 0.0753

Gnomad4 AMR exome AF: 0.00530

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000391

Gnomad4 OTH exome AF: 0.00540

GnomAD4 genome AF: 0.0200 AC: 3035 AN: 151488 Hom.: 93 Cov.: 28 AF XY: 0.0199 AC XY: 1469 AN XY: 73980

Gnomad4 AFR AF: 0.0689

Gnomad4 AMR AF: 0.00780

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00231

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000457

Gnomad4 OTH AF: 0.0138

Alfa AF: 0.00508 Hom.: 6

Bravo AF: 0.0229

ESP6500AA AF: 0.0697 AC: 307

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00753 AC: 914

EpiCase AF: 0.000818

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.70
DEOGEN2	Benign	0.32	T;T;.;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.83	.;T;T;T;T
MetaRNN	Benign	0.0015	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.83	N;N;.;.;.
MutationTaster	Benign	0.92	P;P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.52	N;.;N;.;.
REVEL	Benign	0.076
Sift	Benign	0.70	T;.;T;.;.
Sift4G	Benign	0.98	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.068
MVP		0.22
MPC		0.57
ClinPred		0.0040	T
GERP RS		2.8
Varity_R		0.036
gMVP		0.074

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: rs2230123; hg19: chr17-40451844; COSMIC: COSV99069302; COSMIC: COSV99069302;