rs753913610

Variant names:

• chr11-128484826-G-A
• rs753913610
• NM_001143820.2:c.859C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001143820.2(ETS1):​c.859C>T​(p.Arg287Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,038 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R287L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ETS1 NM_001143820.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44
• Publications: 1 publications found

Genes affected

ETS1 (HGNC:3488): (ETS proto-oncogene 1, transcription factor) This gene encodes a member of the ETS family of transcription factors, which are defined by the presence of a conserved ETS DNA-binding domain that recognizes the core consensus DNA sequence GGAA/T in target genes. These proteins function either as transcriptional activators or repressors of numerous genes, and are involved in stem cell development, cell senescence and death, and tumorigenesis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Jul 2011]

ETS1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 14 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143820.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETS1	NM_001143820.2	MANE Select	c.859C>T	p.Arg287Cys	missense	Exon 7 of 10	NP_001137292.1	P14921-3
	ETS1	NM_005238.4		c.727C>T	p.Arg243Cys	missense	Exon 5 of 8	NP_005229.1	P14921-1
	ETS1	NM_001330451.2		c.727C>T	p.Arg243Cys	missense	Exon 5 of 7	NP_001317380.1	P14921-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETS1	ENST00000392668.8	TSL:1 MANE Select	c.859C>T	p.Arg287Cys	missense	Exon 7 of 10	ENSP00000376436.3	P14921-3
	ETS1	ENST00000319397.7	TSL:1	c.727C>T	p.Arg243Cys	missense	Exon 5 of 8	ENSP00000324578.5	P14921-1
	ETS1	ENST00000531611.5	TSL:1	c.727C>T	p.Arg243Cys	missense	Exon 5 of 7	ENSP00000435666.1	P14921-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250874 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461038 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726716

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000224 AC: 1 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39664

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111398

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.20
Sift	Uncertain	0.010	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.42		Loss of solvent accessibility (P = 0.002)
MVP		0.87
MPC		1.3
ClinPred		0.77	D
GERP RS		5.6
Varity_R		0.29
gMVP		0.56
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs753913610; hg19: chr11-128354721;