2-218981891-C-A

Variant names:

• chr2-218981891-C-A
• rs1391967162
• NM_017521.3:c.493G>T

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.493G>T​(p.Ala165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,090,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A165D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: FEV NM_017521.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• 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=0.05136305).

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.493G>T	p.Ala165Ser	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.493G>T	p.Ala165Ser	missense	Exon 3 of 3	ENSP00000295727.1	Q99581
	LINC00608	ENST00000627043.2	TSL:5	n.1201+2511C>A		intron	N/A
	FEV	ENST00000470119.1	TSL:2	n.*67G>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1090606 Hom.: 0 Cov.: 30 AF XY: 0.00000384 AC XY: 2 AN XY: 520196

African (AFR) AF: 0.00 AC: 0 AN: 22248

American (AMR) AF: 0.00 AC: 0 AN: 7794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13390

East Asian (EAS) AF: 0.00 AC: 0 AN: 24946

South Asian (SAS) AF: 0.0000472 AC: 1 AN: 21192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3232

European-Non Finnish (NFE) AF: 0.00000215 AC: 2 AN: 928798

Other (OTH) AF: 0.00 AC: 0 AN: 43412

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	1.5	N
REVEL	Benign	0.026
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.037	B
Vest4		0.061
MutPred		0.24		Gain of glycosylation at A165 (P = 0.0045)
MVP		0.055
ClinPred		0.14	T
GERP RS		2.7
Varity_R		0.098
gMVP		0.28
Mutation Taster		=75/25	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: rs1391967162; hg19: chr2-219846613;