3-186080097-C-A

Variant names:

• chr3-186080097-C-A
• rs377678658
• NM_004454.3:c.370G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004454.3(ETV5):​c.370G>T​(p.Asp124Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000015 in 1,329,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D124N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ETV5 NM_004454.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.36
• Publications: 0 publications found

Genes affected

ETV5 (HGNC:3494): (ETS variant transcription factor 5) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in cellular response to oxidative stress; negative regulation of transcription by RNA polymerase II; and positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ETV5-AS1 (HGNC:40222): (ETV5 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004454.3. 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
	ETV5	NM_004454.3	MANE Select	c.370G>T	p.Asp124Tyr	missense	Exon 7 of 13	NP_004445.1	P41161-1
	ETV5-AS1	NR_046594.1		n.173-463C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETV5	ENST00000306376.10	TSL:1 MANE Select	c.370G>T	p.Asp124Tyr	missense	Exon 7 of 13	ENSP00000306894.5	P41161-1
	ETV5	ENST00000434744.5	TSL:1	c.370G>T	p.Asp124Tyr	missense	Exon 7 of 13	ENSP00000413755.1	P41161-1
	ETV5	ENST00000875747.1		c.370G>T	p.Asp124Tyr	missense	Exon 7 of 13	ENSP00000545806.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1329668 Hom.: 0 Cov.: 34 AF XY: 0.00000307 AC XY: 2 AN XY: 650626

African (AFR) AF: 0.00 AC: 0 AN: 27626

American (AMR) AF: 0.00 AC: 0 AN: 22178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19590

East Asian (EAS) AF: 0.00 AC: 0 AN: 34186

South Asian (SAS) AF: 0.00 AC: 0 AN: 61138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4936

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1055090

Other (OTH) AF: 0.00 AC: 0 AN: 54926

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.67		Loss of ubiquitination at K126 (P = 0.0228)
MVP		0.56
MPC		0.96
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.70
gMVP		0.68
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs377678658; hg19: chr3-185797886;