Genetic Variant NM_001004341.2:c.664G>A (chr1-157093071-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001004341.2(ETV3L):c.664G>A(p.Val222Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,509,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ETV3L
NM_001004341.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

Publications

0 publications found

Variant links:

Genes affected

ETV3L (HGNC:33834): (ETS variant transcription factor 3 like) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific. Predicted to be involved in cell differentiation and regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ETV3L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0071534812).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004341.2. 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
	ETV3L	NM_001004341.2	MANE Select	c.664G>A	p.Val222Ile	missense	Exon 5 of 5	NP_001004341.1	Q6ZN32

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ETV3L	ENST00000454449.3	TSL:2 MANE Select	c.664G>A	p.Val222Ile	missense	Exon 5 of 5	ENSP00000430271.1	Q6ZN32
ETV3L	ENST00000671886.1		c.664G>A	p.Val222Ile	missense	Exon 6 of 6	ENSP00000500322.1	Q6ZN32
ETV3L	ENST00000671942.1		c.664G>A	p.Val222Ile	missense	Exon 6 of 6	ENSP00000500028.1	Q6ZN32

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000205

AC:

AN:

117214

AF XY:

0.000164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000298

Gnomad ASJ exome

AF:

0.00254

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000162

Gnomad OTH exome

AF:

0.000624

GnomAD4 exome

AF:

0.000110

AC:

150

AN:

1357536

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

664866

show subpopulations

African (AFR)

AF:

0.0000658

AC:

AN:

30374

American (AMR)

AF:

0.000174

AC:

AN:

28742

Ashkenazi Jewish (ASJ)

AF:

0.00190

AC:

AN:

21064

East Asian (EAS)

AF:

0.00

AC:

AN:

36678

South Asian (SAS)

AF:

0.0000141

AC:

AN:

70722

European-Finnish (FIN)

AF:

0.0000207

AC:

AN:

48388

Middle Eastern (MID)

AF:

0.000486

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.0000848

AC:

AN:

1061474

Other (OTH)

AF:

0.000161

AC:

AN:

55978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000234

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000144

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0028

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.34

M_CAP

Benign

0.0023

MetaRNN

Benign

0.0072

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

PhyloP100

1.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.16

REVEL

Benign

0.052

Sift

Benign

0.042

Sift4G

Benign

0.47

Polyphen

0.17

Vest4

0.035

MutPred

0.23

Gain of relative solvent accessibility (P = 0.0522)

MVP

0.34

MPC

0.025

ClinPred

0.034

GERP RS

2.3

Varity_R

0.028

gMVP

0.040

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over