7-122302028-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001024613.4(FEZF1):c.1397T>G(p.Leu466Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,598,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (1 hom.)
• Consequence: FEZF1 NM_001024613.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29

Genes affected

FEZF1 (HGNC:22788): (FEZ family zinc finger 1) This gene encodes a transcriptional repressor that belongs to the zinc finger double domain protein family. The encoded protein is thought to play a role in the embryonic migration of gonadotropin-releasing hormone neurons into the brain. Mutations in this gene are associated with hypogonadotropic hypogonadism-22 with anosmia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.068174124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FEZF1	NM_001024613.4	c.1397T>G	p.Leu466Arg	missense_variant	4/4	ENST00000442488.7
FEZF1	NM_001160264.2	c.1247T>G	p.Leu416Arg	missense_variant	5/5
FEZF1	XM_005250337.4	c.1397T>G	p.Leu466Arg	missense_variant	5/5
FEZF1	XM_011516202.3	c.1247T>G	p.Leu416Arg	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FEZF1	ENST00000442488.7	c.1397T>G	p.Leu466Arg	missense_variant	4/4	1	NM_001024613.4	P2
FEZF1	ENST00000427185.2	c.1247T>G	p.Leu416Arg	missense_variant	5/5	1		A2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

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

GnomAD3 exomes AF: 0.0000516 AC: 12 AN: 232554 Hom.: 1 AF XY: 0.0000468 AC XY: 6 AN XY: 128168

Gnomad AFR exome AF: 0.000569

Gnomad AMR exome AF: 0.000119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1446076 Hom.: 1 Cov.: 31 AF XY: 0.0000153 AC XY: 11 AN XY: 719634

Gnomad4 AFR exome AF: 0.000301

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000668

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74374

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.0000588 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 28, 2022

This variant is present in population databases (rs577039958, gnomAD 0.05%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FEZF1-related conditions. This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 466 of the FEZF1 protein (p.Leu466Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	0.020
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.099
Sift	Benign	0.097	T;T
Sift4G	Uncertain	0.020	D;D
Polyphen		0.65	P;P
Vest4		0.56
MutPred		0.30		Gain of solvent accessibility (P = 0.0365);.;
MVP		0.24
ClinPred		0.050	T
GERP RS		5.1
Varity_R		0.22
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs577039958; hg19: chr7-121942082;