chr3-62371323-G-T

Variant names:

• chr3-62371323-G-T
• NM_018008.4:c.1014C>A

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.1014C>A​(p.Cys338*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FEZF2 NM_018008.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.73
• 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 3-62371323-G-T is Pathogenic according to our data. Variant chr3-62371323-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 3774179.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.1014C>A	p.Cys338*	stop_gained	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.1014C>A	p.Cys338*	stop_gained	Exon 4 of 5	1	NM_018008.4	ENSP00000283268.3
FEZF2	ENST00000475839.1	c.1014C>A	p.Cys338*	stop_gained	Exon 3 of 4	1		ENSP00000418804.1
FEZF2	ENST00000486811.5	c.1014C>A	p.Cys338*	stop_gained	Exon 5 of 6	5		ENSP00000418589.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 21, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		2.7
Vest4		0.86
GERP RS		5.3
Mutation Taster		=4/196	disease causing (fs/PTC)

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: chr3-62356998;