rs597570

chr11-125481576-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005103.5(FEZ1):c.369T>A(p.Asp123Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,611,700 control chromosomes in the GnomAD database, including 26,699 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (2762 hom., cov: 32)
  • Exomes 𝑓: 0.18 (23937 hom.)
• Consequence: FEZ1 NM_005103.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.30

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013558865).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FEZ1	NM_005103.5	c.369T>A	p.Asp123Glu	missense_variant	3/10	ENST00000278919.8
FEZ1	XM_005271734.3	c.369T>A	p.Asp123Glu	missense_variant	3/10
FEZ1	XM_005271735.3	c.369T>A	p.Asp123Glu	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FEZ1	ENST00000278919.8	c.369T>A	p.Asp123Glu	missense_variant	3/10	1	NM_005103.5	P1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28186 AN: 152018 Hom.: 2756 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0709

Gnomad SAS AF: 0.0763

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.154 AC: 38686 AN: 251410 Hom.: 3447 AF XY: 0.151 AC XY: 20461 AN XY: 135872

Gnomad AFR exome AF: 0.215

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.0637

Gnomad SAS exome AF: 0.0714

Gnomad FIN exome AF: 0.228

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.176 AC: 256516 AN: 1459564 Hom.: 23937 Cov.: 30 AF XY: 0.173 AC XY: 125489 AN XY: 726242

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.166

Gnomad4 EAS exome AF: 0.0797

Gnomad4 SAS exome AF: 0.0717

Gnomad4 FIN exome AF: 0.227

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.185 AC: 28220 AN: 152136 Hom.: 2762 Cov.: 32 AF XY: 0.184 AC XY: 13674 AN XY: 74372

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.0710

Gnomad4 SAS AF: 0.0768

Gnomad4 FIN AF: 0.237

Gnomad4 NFE AF: 0.183

Gnomad4 OTH AF: 0.180

Alfa AF: 0.177 Hom.: 1823

Bravo AF: 0.182

TwinsUK AF: 0.200 AC: 742

ALSPAC AF: 0.208 AC: 803

ESP6500AA AF: 0.216 AC: 951

ESP6500EA AF: 0.186 AC: 1601

ExAC AF: 0.157 AC: 18999

Asia WGS AF: 0.0940 AC: 327 AN: 3478

EpiCase AF: 0.177

EpiControl AF: 0.184

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.099	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.0051	P
PrimateAI	Benign	0.40	T
Polyphen		0.13	B;B
Vest4		0.085
MutPred		0.36		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MPC		0.36
ClinPred		0.014	T
GERP RS		3.0
Varity_R		0.053
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs597570; hg19: chr11-125351472; COSMIC: COSV54030673;