3-62372066-C-CCT

Variant names:

• chr3-62372066-C-CCT
• NM_018008.4:c.801_802dupAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018008.4(FEZF2):​c.801_802dupAG​(p.Gly268GlufsTer115) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FEZF2 NM_018008.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.124
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-62372066-C-CCT is Pathogenic according to our data. Variant chr3-62372066-C-CCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3367203.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FEZF2	NM_018008.4	c.801_802dupAG	p.Gly268GlufsTer115	frameshift_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.801_802dupAG	p.Gly268GlufsTer115	frameshift_variant	Exon 2 of 5	1	NM_018008.4	ENSP00000283268.3
FEZF2	ENST00000475839.1	c.801_802dupAG	p.Gly268GlufsTer115	frameshift_variant	Exon 1 of 4	1		ENSP00000418804.1
FEZF2	ENST00000486811.5	c.801_802dupAG	p.Gly268GlufsTer115	frameshift_variant	Exon 3 of 6	5		ENSP00000418589.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental phenotype Pathogenic:1

Oct 28, 2024

Institute of Human Genetics, University of Goettingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant c.801_802dup (p.(Gly268Glufs*115)) in exon 2 of the FEZF2 gene is not found in the gnomAD database and changes the protein sequence at position Gly268, the new reading frame ends in a STOP codon at position 115 and thus interrupts the reading frame prematurely. Truncating variants in FEZF2 were described to be a mechanism of disease (PMID: 38425142; gnomAD 4.1.0 pLI-score = 1). This truncating variant was found to be de novo in our patient, with confirmed maternity and paternity. Patient also carried a de novo likely pathogenic KMT2B Variant (NM_014727.3:c.5221G>A, p.Gly1741Ser). ACMG criteria used for classification: PVS1_STR, PS2, PM2_SUP. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr3-62357741;