21-38819538-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005239.6(ETS2):c.847G>A(p.Ala283Thr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A283V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ETS2 NM_005239.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.545

Genes affected

ETS2 (HGNC:3489): (ETS proto-oncogene 2, transcription factor) This gene encodes a transcription factor which regulates genes involved in development and apoptosis. The encoded protein is also a protooncogene and shown to be involved in regulation of telomerase. A pseudogene of this gene is located on the X chromosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

ETS2-AS1 (HGNC:56712): (ETS2 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03926274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ETS2	NM_005239.6	c.847G>A	p.Ala283Thr	missense_variant	8/10	ENST00000360938.8
ETS2	NM_001256295.2	c.1267G>A	p.Ala423Thr	missense_variant	9/11
ETS2	XM_005260935.2	c.847G>A	p.Ala283Thr	missense_variant	8/10
ETS2	XM_017028290.2	c.847G>A	p.Ala283Thr	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ETS2	ENST00000360938.8	c.847G>A	p.Ala283Thr	missense_variant	8/10	1	NM_005239.6	P1
ETS2-AS1	ENST00000663561.1	n.535-6113C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 33

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

Dec 18, 2023

The c.847G>A (p.A283T) alteration is located in exon 8 (coding exon 7) of the ETS2 gene. This alteration results from a G to A substitution at nucleotide position 847, causing the alanine (A) at amino acid position 283 to be replaced by a threonine (T). 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	Benign	0.060
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.72
Dann	Benign	0.85
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.53	T;.
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.44	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.0070
Sift	Benign	0.47	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.0	B;B
Vest4		0.046
MutPred		0.23		Gain of glycosylation at A283 (P = 0.027);Gain of glycosylation at A283 (P = 0.027);
MVP		0.17
MPC		0.30
ClinPred		0.024	T
GERP RS		1.5
Varity_R		0.017
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-40191462;