NM_017521.3:c.610G>C

Variant names:

• chr2-218981774-C-G
• rs916509509
• NM_017521.3:c.610G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_017521.3(FEV):​c.610G>C​(p.Ala204Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 151,658 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FEV NM_017521.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20628235).

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.610G>C	p.Ala204Pro	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.610G>C	p.Ala204Pro	missense	Exon 3 of 3	ENSP00000295727.1	Q99581
	LINC00608	ENST00000627043.2	TSL:5	n.1201+2394C>G		intron	N/A
	FEV	ENST00000470119.1	TSL:2	n.*184G>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151658 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000411

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000628 AC: 7 AN: 1114348 Hom.: 0 Cov.: 31 AF XY: 0.00000188 AC XY: 1 AN XY: 533288

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000218 AC: 5 AN: 22936

American (AMR) AF: 0.00 AC: 0 AN: 8458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14574

East Asian (EAS) AF: 0.00 AC: 0 AN: 26780

South Asian (SAS) AF: 0.00 AC: 0 AN: 25674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3196

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 945110

Other (OTH) AF: 0.0000445 AC: 2 AN: 44930

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000105196), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151658 Hom.: 0 Cov.: 33 AF XY: 0.0000810 AC XY: 6 AN XY: 74092

African (AFR) AF: 0.000411 AC: 17 AN: 41340

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67834

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000121

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	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.084
Sift	Benign	0.27	T
Sift4G	Benign	0.25	T
Polyphen		0.56	P
Vest4		0.42
MutPred		0.39		Gain of loop (P = 0.0051)
MVP		0.076
ClinPred		0.14	T
GERP RS		2.8
Varity_R		0.14
gMVP		0.41
Mutation Taster		=85/15	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: rs916509509; hg19: chr2-219846496;