rs597570

Variant names:

• chr11-125481576-A-T
• rs597570
• NM_005103.5:c.369T>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 32 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005103.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FEZ1	NM_005103.5	MANE Select	c.369T>A	p.Asp123Glu	missense	Exon 3 of 10	NP_005094.1	Q99689-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FEZ1	ENST00000278919.8	TSL:1 MANE Select	c.369T>A	p.Asp123Glu	missense	Exon 3 of 10	ENSP00000278919.3	Q99689-1
	FEZ1	ENST00000965005.1		c.369T>A	p.Asp123Glu	missense	Exon 3 of 11	ENSP00000635064.1
	FEZ1	ENST00000863680.1		c.369T>A	p.Asp123Glu	missense	Exon 3 of 10	ENSP00000533739.1

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

GnomAD2 exomes AF: 0.154 AC: 38686 AN: 251410 AF XY: 0.151

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 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

African (AFR) AF: 0.221 AC: 7374 AN: 33418

American (AMR) AF: 0.112 AC: 5023 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 4338 AN: 26124

East Asian (EAS) AF: 0.0797 AC: 3163 AN: 39694

South Asian (SAS) AF: 0.0717 AC: 6186 AN: 86222

European-Finnish (FIN) AF: 0.227 AC: 12111 AN: 53416

Middle Eastern (MID) AF: 0.166 AC: 925 AN: 5586

European-Non Finnish (NFE) AF: 0.187 AC: 207088 AN: 1110092

Other (OTH) AF: 0.171 AC: 10308 AN: 60292

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

African (AFR) AF: 0.218 AC: 9039 AN: 41492

American (AMR) AF: 0.137 AC: 2088 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3470

East Asian (EAS) AF: 0.0710 AC: 368 AN: 5180

South Asian (SAS) AF: 0.0768 AC: 370 AN: 4818

European-Finnish (FIN) AF: 0.237 AC: 2509 AN: 10582

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12467 AN: 67984

Other (OTH) AF: 0.180 AC: 380 AN: 2114

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 v4.9

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
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.019
Sift	Benign	0.40	T
Sift4G	Benign	1.0	T
Polyphen		0.13	B
Vest4		0.085
MutPred		0.36		Gain of helix (P = 0.062)
MPC		0.36
ClinPred		0.014	T
GERP RS		3.0
PromoterAI		-0.011	Neutral
Varity_R		0.053
gMVP		0.12
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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