7-122302261-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001024613.4(FEZF1):c.1164C>T(p.Thr388=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000654 in 1,614,220 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T388T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (7 hom.)
• Consequence: FEZF1 NM_001024613.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.309

Genes affected

FEZF1 (HGNC:22788): (FEZ family zinc finger 1) This gene encodes a transcriptional repressor that belongs to the zinc finger double domain protein family. The encoded protein is thought to play a role in the embryonic migration of gonadotropin-releasing hormone neurons into the brain. Mutations in this gene are associated with hypogonadotropic hypogonadism-22 with anosmia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 7-122302261-G-A is Benign according to our data. Variant chr7-122302261-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 741676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.309 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FEZF1	NM_001024613.4	c.1164C>T	p.Thr388=	synonymous_variant	4/4	ENST00000442488.7
FEZF1	NM_001160264.2	c.1014C>T	p.Thr338=	synonymous_variant	5/5
FEZF1	XM_005250337.4	c.1164C>T	p.Thr388=	synonymous_variant	5/5
FEZF1	XM_011516202.3	c.1014C>T	p.Thr338=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FEZF1	ENST00000442488.7	c.1164C>T	p.Thr388=	synonymous_variant	4/4	1	NM_001024613.4	P2
FEZF1	ENST00000427185.2	c.1014C>T	p.Thr338=	synonymous_variant	5/5	1		A2

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00112 AC: 282 AN: 251486 Hom.: 2 AF XY: 0.00132 AC XY: 180 AN XY: 135922

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00503

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000673 AC: 984 AN: 1461894 Hom.: 7 Cov.: 31 AF XY: 0.000814 AC XY: 592 AN XY: 727248

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00715

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00483

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000252

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74478

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000916 Hom.: 0

Bravo AF: 0.000408

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 23, 2021

- -

FEZF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	5.2
Dann	Benign	0.82

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: rs142377395; hg19: chr7-121942315;