Variant 11-125489474-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005103.5(FEZ1):c.304G>A(p.Asp102Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,459,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

FEZ1
NM_005103.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.70

Variant links:

Genes affected

FEZ1 (HGNC:3659): (fasciculation and elongation protein zeta 1) This gene is an ortholog of the C. elegans unc-76 gene, which is necessary for normal axonal bundling and elongation within axon bundles. Expression of this gene in C. elegans unc-76 mutants can restore to the mutants partial locomotion and axonal fasciculation, suggesting that it also functions in axonal outgrowth. The N-terminal half of the gene product is highly acidic. Alternatively spliced transcript variants encoding different isoforms of this protein have been described. [provided by RefSeq, Jul 2008]

FEZ1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FEZ1	NM_005103.5 linkuse as main transcript	c.304G>A	p.Asp102Asn	missense_variant	2/10	ENST00000278919.8
FEZ1	NM_022549.4 linkuse as main transcript	c.304G>A	p.Asp102Asn	missense_variant	2/2
FEZ1	XM_005271734.3 linkuse as main transcript	c.304G>A	p.Asp102Asn	missense_variant	2/10
FEZ1	XM_005271735.3 linkuse as main transcript	c.304G>A	p.Asp102Asn	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FEZ1	ENST00000278919.8 linkuse as main transcript	c.304G>A	p.Asp102Asn	missense_variant	2/10	1	NM_005103.5	P1	Q99689-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1459872

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2022

The c.304G>A (p.D102N) alteration is located in exon 2 (coding exon 1) of the FEZ1 gene. This alteration results from a G to A substitution at nucleotide position 304, causing the aspartic acid (D) at amino acid position 102 to be replaced by an asparagine (N). 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

0.25

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;T;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

.;D;.;T

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.69

D;D;D;D

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.2

M;M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.8

.;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.15

.;T;D;D

Sift4G

Benign

0.14

.;T;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.66, 0.64, 0.67

MutPred

0.65

Loss of phosphorylation at T99 (P = 0.1185);Loss of phosphorylation at T99 (P = 0.1185);Loss of phosphorylation at T99 (P = 0.1185);Loss of phosphorylation at T99 (P = 0.1185);

MVP

0.58

MPC

1.0

ClinPred

0.89

GERP RS

5.4

Varity_R

0.18

gMVP

0.55

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over