11-125489670-G-T

Position:

• chr11-125489670-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005103.5(FEZ1):​c.108C>A​(p.His36Gln) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FEZ1 NM_005103.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.107

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062161118).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FEZ1	NM_005103.5	c.108C>A	p.His36Gln	missense_variant	2/10	ENST00000278919.8
FEZ1	NM_022549.4	c.108C>A	p.His36Gln	missense_variant	2/2
FEZ1	XM_005271734.3	c.108C>A	p.His36Gln	missense_variant	2/10
FEZ1	XM_005271735.3	c.108C>A	p.His36Gln	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FEZ1	ENST00000278919.8	c.108C>A	p.His36Gln	missense_variant	2/10	1	NM_005103.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2023

The c.108C>A (p.H36Q) alteration is located in exon 2 (coding exon 1) of the FEZ1 gene. This alteration results from a C to A substitution at nucleotide position 108, causing the histidine (H) at amino acid position 36 to be replaced by a glutamine (Q). 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	0.065
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.054	T;T;.;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.52	.;T;.;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.062	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;N;.
MutationTaster	Benign	0.76	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.70	.;N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.61	.;T;T;T;T
Sift4G	Benign	0.38	.;T;T;T;T
Polyphen		0.023	B;B;.;.;.
Vest4		0.083, 0.075, 0.072
MutPred		0.13		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.45
MPC		0.31
ClinPred		0.086	T
GERP RS		2.9
Varity_R		0.029
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-125359566;