3-62371247-C-T

Variant names:

• chr3-62371247-C-T
• NM_018008.4:c.1090G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018008.4(FEZF2):​c.1090G>A​(p.Glu364Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FEZF2 NM_018008.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

FEZF2 (HGNC:13506): (FEZ family zinc finger 2) Predicted to enable transcription cis-regulatory region binding activity. Predicted to be involved in positive regulation of transcription, DNA-templated. Predicted to act upstream of or within several processes, including negative regulation of transcription by RNA polymerase II; nervous system development; and regulation of neuron differentiation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FEZF2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FEZF2	NM_018008.4	c.1090G>A	p.Glu364Lys	missense_variant	Exon 4 of 5	ENST00000283268.8	NP_060478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FEZF2	ENST00000283268.8	c.1090G>A	p.Glu364Lys	missense_variant	Exon 4 of 5	1	NM_018008.4	ENSP00000283268.3
FEZF2	ENST00000475839.1	c.1090G>A	p.Glu364Lys	missense_variant	Exon 3 of 4	1		ENSP00000418804.1
FEZF2	ENST00000486811.5	c.1090G>A	p.Glu364Lys	missense_variant	Exon 5 of 6	5		ENSP00000418589.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

FEZF2-related disorder Uncertain:1

Dec 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FEZF2 c.1090G>A variant is predicted to result in the amino acid substitution p.Glu364Lys. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	.;.;D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L;L;L
PhyloP100		7.9
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.060	T;T;T
Sift4G	Uncertain	0.036	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.74
MutPred		0.38		Gain of methylation at E364 (P = 0);Gain of methylation at E364 (P = 0);Gain of methylation at E364 (P = 0);
MVP		0.47
MPC		2.9
ClinPred		0.95	D
GERP RS		6.1
Varity_R		0.71
gMVP		0.90
Mutation Taster		=12/88	disease causing

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

hg19: chr3-62356922; COSMIC: COSV51862718; COSMIC: COSV51862718;