Genetic Variant FEZF2:p.Ala165Ser (chr3-62372376-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018008.4(FEZF2):c.493G>T(p.Ala165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A165T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FEZF2
NM_018008.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.65

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.093526125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FEZF2	NM_018008.4 link	c.493G>T	p.Ala165Ser	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.493G>T	p.Ala165Ser	missense_variant	Exon 2 of 5	1	NM_018008.4	ENSP00000283268.3	Q8TBJ5-1
FEZF2	ENST00000475839.1 link	c.493G>T	p.Ala165Ser	missense_variant	Exon 1 of 4	1		ENSP00000418804.1	Q8TBJ5-1
FEZF2	ENST00000486811.5 link	c.493G>T	p.Ala165Ser	missense_variant	Exon 3 of 6	5		ENSP00000418589.1	Q8TBJ5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459008

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725968

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111778

Other (OTH)

AF:

0.00

AC:

AN:

60300

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

T;T;T

Eigen

Benign

-0.16

Eigen_PC

Benign

0.030

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.70

.;.;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.094

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;L;L

PhyloP100

1.7

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.93

N;N;N

REVEL

Benign

0.066

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.010

B;B;B

Vest4

0.16

MutPred

0.53

Gain of disorder (P = 0.094);Gain of disorder (P = 0.094);Gain of disorder (P = 0.094);

MVP

0.18

MPC

1.1

ClinPred

0.58

GERP RS

5.2

Varity_R

0.18

gMVP

0.14

Mutation Taster

=93/7

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

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3-62372376-C-A

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