Genetic Variant FEZF2:p.Ala251Thr (chr3-62372118-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018008.4(FEZF2):c.751G>A(p.Ala251Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,601,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. A251S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FEZF2
NM_018008.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.146

Publications

0 publications found

Variant links:

Genes affected

FEZF2 (HGNC:13506): (FEZ family zinc finger 2) Predicted to enable transcription cis-regulatory region binding activity. Predicted to be involved in positive regulation of transcription, DNA-templated. Predicted to act upstream of or within several processes, including negative regulation of transcription by RNA polymerase II; nervous system development; and regulation of neuron differentiation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FEZF2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

FEZF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046683222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FEZF2	NM_018008.4 link	c.751G>A	p.Ala251Thr	missense_variant	Exon 2 of 5	ENST00000283268.8	NP_060478.3	Q8TBJ5-1A0A140VKG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FEZF2	ENST00000283268.8 link	c.751G>A	p.Ala251Thr	missense_variant	Exon 2 of 5	1	NM_018008.4	ENSP00000283268.3	Q8TBJ5-1
FEZF2	ENST00000475839.1 link	c.751G>A	p.Ala251Thr	missense_variant	Exon 1 of 4	1		ENSP00000418804.1	Q8TBJ5-1
FEZF2	ENST00000486811.5 link	c.751G>A	p.Ala251Thr	missense_variant	Exon 3 of 6	5		ENSP00000418589.1	Q8TBJ5-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

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

GnomAD2 exomes

AF:

0.00000452

AC:

AN:

221048

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000615

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449656

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33352

American (AMR)

AF:

0.00

AC:

AN:

42626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25808

East Asian (EAS)

AF:

0.0000510

AC:

AN:

39218

South Asian (SAS)

AF:

0.00

AC:

AN:

84170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106906

Other (OTH)

AF:

0.00

AC:

AN:

59920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000825

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.17

T;T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.61

.;.;T

M_CAP

Benign

0.0079

MetaRNN

Benign

0.047

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;N;N

PhyloP100

0.15

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.043

Sift

Benign

0.25

T;T;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.044

MutPred

0.22

Gain of methylation at K247 (P = 0.0975);Gain of methylation at K247 (P = 0.0975);Gain of methylation at K247 (P = 0.0975);

MVP

0.15

MPC

0.50

ClinPred

0.21

GERP RS

3.4

Varity_R

0.081

gMVP

0.24

Mutation Taster

=86/14

polymorphism

(source)

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

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

3-62372118-C-T

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