3-62372118-C-A

Variant names:

• chr3-62372118-C-A
• rs750230837
• NM_018008.4:c.751G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018008.4(FEZF2):​c.751G>T​(p.Ala251Ser) 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: 0.146
• 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: 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=0.06074366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FEZF2	NM_018008.4	c.751G>T	p.Ala251Ser	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.751G>T	p.Ala251Ser	missense_variant	Exon 2 of 5	1	NM_018008.4	ENSP00000283268.3
FEZF2	ENST00000475839.1	c.751G>T	p.Ala251Ser	missense_variant	Exon 1 of 4	1		ENSP00000418804.1
FEZF2	ENST00000486811.5	c.751G>T	p.Ala251Ser	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

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.751G>T (p.A251S) alteration is located in exon 2 (coding exon 1) of the FEZF2 gene. This alteration results from a G to T substitution at nucleotide position 751, causing the alanine (A) at amino acid position 251 to be replaced by a serine (S). 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	0.092
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	10
DANN	Benign	0.88
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.55	.;.;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N;N;N
PhyloP100		0.15
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.61	N;N;N
REVEL	Benign	0.055
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.087
MutPred		0.24		Gain of phosphorylation at A251 (P = 0.0519);Gain of phosphorylation at A251 (P = 0.0519);Gain of phosphorylation at A251 (P = 0.0519);
MVP		0.19
MPC		0.47
ClinPred		0.12	T
GERP RS		3.4
Varity_R		0.076
gMVP		0.18
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs750230837; hg19: chr3-62357793;