chr11-125452358-C-G

Position:

• chr11-125452358-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005103.5(FEZ1):​c.1072G>C​(p.Glu358Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,612,482 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (11 hom., cov: 32)
  • Exomes 𝑓: 0.015 (212 hom.)
• Consequence: FEZ1 NM_005103.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.42

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008377522).
• BP6: Variant 11-125452358-C-G is Benign according to our data. Variant chr11-125452358-C-G is described in ClinVar as [Benign]. Clinvar id is 786218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.011 (1673/152266) while in subpopulation NFE AF= 0.0172 (1171/68018). AF 95% confidence interval is 0.0164. There are 11 homozygotes in gnomad4. There are 755 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FEZ1	NM_005103.5	c.1072G>C	p.Glu358Gln	missense_variant	8/10	ENST00000278919.8
FEZ1	XM_005271734.3	c.1072G>C	p.Glu358Gln	missense_variant	8/10
FEZ1	XM_005271735.3	c.1072G>C	p.Glu358Gln	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FEZ1	ENST00000278919.8	c.1072G>C	p.Glu358Gln	missense_variant	8/10	1	NM_005103.5	P1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1674 AN: 152148 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.0103 AC: 2595 AN: 251432 Hom.: 17 AF XY: 0.0103 AC XY: 1406 AN XY: 135896

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0104

GnomAD4 exome AF: 0.0151 AC: 22030 AN: 1460216 Hom.: 212 Cov.: 29 AF XY: 0.0148 AC XY: 10735 AN XY: 726584

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00201

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.0110 AC: 1673 AN: 152266 Hom.: 11 Cov.: 32 AF XY: 0.0101 AC XY: 755 AN XY: 74468

Gnomad4 AFR AF: 0.00298

Gnomad4 AMR AF: 0.00766

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0158

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.0148 Hom.: 14

Bravo AF: 0.0102

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0236 AC: 91

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0166 AC: 143

ExAC AF: 0.00978 AC: 1187

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0164

EpiControl AF: 0.0136

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	.;D
MetaRNN	Benign	0.0084	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.90	.;N
REVEL	Benign	0.10
Sift	Benign	0.52	.;T
Sift4G	Benign	0.52	.;T
Polyphen		0.85	P;P
Vest4		0.37
MPC		0.70
ClinPred		0.015	T
GERP RS		5.0
Varity_R		0.40
gMVP		0.37

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

Other links and lift over

dbSNP: rs112732577; hg19: chr11-125322254; COSMIC: COSV99073929; COSMIC: COSV99073929;