Genetic Variant NM_017521.3:c.413C>G (chr2-218981971-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017521.3(FEV):c.413C>G(p.Pro138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,564,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. P138Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

FEV
NM_017521.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.58

Publications

0 publications found

Variant links:

Genes affected

FEV (HGNC:18562): (FEV transcription factor, ETS family member) This gene belongs to the ETS transcription factor family. ETS family members have a highly conserved 85-amino acid ETS domain that binds purine-rich DNA sequences. The alanine-rich C-terminus of this gene indicates that it may act as a transcription repressor. This gene is exclusively expressed in neurons of the central serotonin (5-HT) system, a system implicated in the pathogeny of such psychiatric diseases as depression, anxiety, and eating disorders. In some types of Ewing tumors, this gene is fused to the Ewing sarcoma (EWS) gene following chromosome translocations. [provided by RefSeq, Jul 2008]

FEV links:

LINC00608 (HGNC:27179): (long intergenic non-protein coding RNA 608)

LINC00608 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22636259).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FEV	NM_017521.3 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 3 of 3	ENST00000295727.2	NP_059991.1	Q99581
FEV	XM_047444822.1 link	c.128C>G	p.Pro43Arg	missense_variant	Exon 3 of 3		XP_047300778.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FEV	ENST00000295727.2 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 3 of 3	1	NM_017521.3	ENSP00000295727.1	Q99581
FEV	ENST00000470119.1 link	n.531C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2
LINC00608	ENST00000627043.2 link	n.1201+2591G>C		intron_variant	Intron 4 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151750

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000989

AC:

AN:

202164

AF XY:

0.0000178

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000215

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000134

AC:

AN:

1412960

Hom.:

Cov.:

AF XY:

0.0000128

AC XY:

AN XY:

702540

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29514

American (AMR)

AF:

0.00

AC:

AN:

38044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24756

East Asian (EAS)

AF:

0.00

AC:

AN:

33382

South Asian (SAS)

AF:

0.00

AC:

AN:

80740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5214

European-Non Finnish (NFE)

AF:

0.0000174

AC:

AN:

1092290

Other (OTH)

AF:

0.00

AC:

AN:

58022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.00000659

AC:

AN:

151750

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74114

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41400

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67898

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000286

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000249

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.18

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

3.6

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.82

REVEL

Benign

0.055

Sift

Benign

0.26

Sift4G

Benign

0.52

Polyphen

0.74

Vest4

0.24

MutPred

0.31

Loss of glycosylation at P138 (P = 0.004);

MVP

0.25

ClinPred

0.14

GERP RS

3.4

Varity_R

0.16

gMVP

0.31

Mutation Taster

=89/11

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over