chr3-62372111-G-A

Variant names:

• chr3-62372111-G-A
• NM_018008.4:c.758C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018008.4(FEZF2):​c.758C>T​(p.Thr253Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FEZF2 NM_018008.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13852024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FEZF2	NM_018008.4	c.758C>T	p.Thr253Ile	missense_variant	Exon 2 of 5	ENST00000283268.8	NP_060478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FEZF2	ENST00000283268.8	c.758C>T	p.Thr253Ile	missense_variant	Exon 2 of 5	1	NM_018008.4	ENSP00000283268.3
FEZF2	ENST00000475839.1	c.758C>T	p.Thr253Ile	missense_variant	Exon 1 of 4	1		ENSP00000418804.1
FEZF2	ENST00000486811.5	c.758C>T	p.Thr253Ile	missense_variant	Exon 3 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: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.758C>T (p.T253I) alteration is located in exon 2 (coding exon 1) of the FEZF2 gene. This alteration results from a C to T substitution at nucleotide position 758, causing the threonine (T) at amino acid position 253 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.69	.;.;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L
PhyloP100		2.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.027
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.013	B;B;B
Vest4		0.43
MutPred		0.50		Loss of phosphorylation at T253 (P = 0.0546);Loss of phosphorylation at T253 (P = 0.0546);Loss of phosphorylation at T253 (P = 0.0546);
MVP		0.13
MPC		0.56
ClinPred		0.22	T
GERP RS		2.2
Varity_R		0.070
gMVP		0.23
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr3-62357786;