chr7-122303975-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001024613.4(FEZF1):​c.463C>T​(p.His155Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,587,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

FEZF1
NM_001024613.4 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67
Variant links:
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]
FEZF1-AS1 (HGNC:41001): (FEZF1 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.30204237).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FEZF1NM_001024613.4 linkuse as main transcriptc.463C>T p.His155Tyr missense_variant 1/4 ENST00000442488.7 NP_001019784.2
FEZF1-AS1NR_036484.1 linkuse as main transcriptn.318G>A non_coding_transcript_exon_variant 1/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FEZF1ENST00000442488.7 linkuse as main transcriptc.463C>T p.His155Tyr missense_variant 1/41 NM_001024613.4 ENSP00000411145 P2A0PJY2-1
FEZF1ENST00000427185.2 linkuse as main transcriptc.429+34C>T intron_variant 1 ENSP00000392727 A2A0PJY2-2
FEZF1-AS1ENST00000428449.5 linkuse as main transcriptn.318G>A non_coding_transcript_exon_variant 1/72

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000150
AC:
3
AN:
200532
Hom.:
0
AF XY:
0.0000184
AC XY:
2
AN XY:
108566
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000105
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000418
AC:
6
AN:
1435562
Hom.:
0
Cov.:
33
AF XY:
0.00000562
AC XY:
4
AN XY:
712018
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000150
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000830
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 25, 2022The c.463C>T (p.H155Y) alteration is located in exon 1 (coding exon 1) of the FEZF1 gene. This alteration results from a C to T substitution at nucleotide position 463, causing the histidine (H) at amino acid position 155 to be replaced by a tyrosine (Y). 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
0.20
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.42
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.19
T
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.83
T
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.30
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-1.5
N
REVEL
Benign
0.19
Sift
Benign
0.039
D
Sift4G
Benign
0.14
T
Polyphen
0.93
P
Vest4
0.50
MutPred
0.61
Gain of loop (P = 0.0195);
MVP
0.33
ClinPred
0.65
D
GERP RS
4.7
Varity_R
0.38
gMVP
0.46

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs747228982; hg19: chr7-121944029; API