Genetic Variant FEZF1:p.His278Asn (chr7-122303281-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_001024613.4(FEZF1):c.832C>A(p.His278Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H278Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FEZF1
NM_001024613.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.95

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 22 with or without anosmia
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FEZF1 links:

ENSG00000293696 (HGNC:):

ENSG00000293696 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-122303281-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 156219.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FEZF1	NM_001024613.4 link	c.832C>A	p.His278Asn	missense_variant	Exon 2 of 4	ENST00000442488.7	NP_001019784.2
FEZF1	NM_001160264.2 link	c.682C>A	p.His228Asn	missense_variant	Exon 3 of 5		NP_001153736.1
FEZF1	XM_005250337.4 link	c.832C>A	p.His278Asn	missense_variant	Exon 3 of 5		XP_005250394.1
FEZF1	XM_011516202.3 link	c.682C>A	p.His228Asn	missense_variant	Exon 4 of 6		XP_011514504.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
FEZF1	ENST00000442488.7 link	c.832C>A	p.His278Asn	missense_variant	Exon 2 of 4	1	NM_001024613.4	ENSP00000411145.2
FEZF1	ENST00000427185.2 link	c.682C>A	p.His228Asn	missense_variant	Exon 3 of 5	1		ENSP00000392727.2
ENSG00000293696	ENST00000718494.1 link	n.390+7446G>T		intron_variant	Intron 4 of 8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;T

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.8

H;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0050

D;D

Vest4

0.87

ClinPred

1.0

GERP RS

5.2

Varity_R

0.98

gMVP

0.89

Mutation Taster

=25/75

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over