chr2-218981681-C-T

Variant names:

• chr2-218981681-C-T
• rs776082147
• NM_017521.3:c.703G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017521.3(FEV):​c.703G>A​(p.Gly235Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000209 in 1,339,806 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: FEV NM_017521.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15
• Publications: 0 publications found

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]

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

ACMG classification

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=0.05924362).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017521.3. 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
	FEV	NM_017521.3	MANE Select	c.703G>A	p.Gly235Ser	missense	Exon 3 of 3	NP_059991.1	Q99581

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FEV	ENST00000295727.2	TSL:1 MANE Select	c.703G>A	p.Gly235Ser	missense	Exon 3 of 3	ENSP00000295727.1	Q99581
	LINC00608	ENST00000627043.2	TSL:5	n.1201+2301C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 26 AN: 1187592 Hom.: 0 Cov.: 30 AF XY: 0.0000190 AC XY: 11 AN XY: 577670

African (AFR) AF: 0.00 AC: 0 AN: 24110

American (AMR) AF: 0.00 AC: 0 AN: 12186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17376

East Asian (EAS) AF: 0.00 AC: 0 AN: 27578

South Asian (SAS) AF: 0.00 AC: 0 AN: 43262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4444

European-Non Finnish (NFE) AF: 0.0000254 AC: 25 AN: 983246

Other (OTH) AF: 0.0000207 AC: 1 AN: 48222

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ClinVar

ClinVar submissions

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	0.083
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.059
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.10
MutPred		0.16		Gain of glycosylation at G235 (P = 0.002)
MVP		0.061
ClinPred		0.44	T
GERP RS		3.7
Varity_R		0.096
gMVP		0.31
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs776082147; hg19: chr2-219846403;