NM_016263.4:c.797T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_016263.4(FZR1):c.797T>C(p.Met266Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000967 in 1,550,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

FZR1
NM_016263.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.63

Publications

2 publications found

Variant links:

Genes affected

FZR1 (HGNC:24824): (fizzy and cell division cycle 20 related 1) Predicted to enable anaphase-promoting complex binding activity and ubiquitin ligase activator activity. Involved in anaphase-promoting complex-dependent catabolic process; mitotic G2 DNA damage checkpoint signaling; and positive regulation of protein metabolic process. Located in nuclear membrane and nucleoplasm. Colocalizes with anaphase-promoting complex. [provided by Alliance of Genome Resources, Apr 2022]

FZR1 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy 109
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

FZR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.6413 (above the threshold of 3.09). Trascript score misZ: 3.0028 (below the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy 109.

BP4

Computational evidence support a benign effect (MetaRNN=0.026036173).

BS2

High AC in GnomAd4 at 43 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FZR1	NM_016263.4	MANE Select	c.797T>C	p.Met266Thr	missense	Exon 9 of 14	NP_057347.2
FZR1	NM_001136198.1		c.797T>C	p.Met266Thr	missense	Exon 8 of 13	NP_001129670.1	Q9UM11-1
FZR1	NM_001136197.1		c.530T>C	p.Met177Thr	missense	Exon 6 of 11	NP_001129669.1	Q9UM11-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FZR1	ENST00000441788.7	TSL:1 MANE Select	c.797T>C	p.Met266Thr	missense	Exon 9 of 14	ENSP00000410369.1	Q9UM11-2
FZR1	ENST00000395095.7	TSL:1	c.797T>C	p.Met266Thr	missense	Exon 8 of 13	ENSP00000378529.2	Q9UM11-1
FZR1	ENST00000313639.8	TSL:1	c.530T>C	p.Met177Thr	missense	Exon 6 of 11	ENSP00000321800.7	Q9UM11-3

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000897

AC:

AN:

156010

AF XY:

0.0000731

show subpopulations

Gnomad AFR exome

AF:

0.000458

Gnomad AMR exome

AF:

0.000162

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000664

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.0000765

AC:

107

AN:

1398136

Hom.:

Cov.:

AF XY:

0.0000725

AC XY:

AN XY:

689632

show subpopulations

African (AFR)

AF:

0.000760

AC:

AN:

31590

American (AMR)

AF:

0.000196

AC:

AN:

35626

Ashkenazi Jewish (ASJ)

AF:

0.000159

AC:

AN:

25148

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.00

AC:

AN:

79210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48544

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.0000612

AC:

AN:

1078768

Other (OTH)

AF:

0.0000863

AC:

AN:

57952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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

AF:

0.000282

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41572

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68002

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000243

Hom.:

Bravo

AF:

0.000298

ESP6500AA

AF:

0.000504

AC:

ESP6500EA

AF:

0.000129

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.13

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.67

M_CAP

Benign

0.022

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.0

PhyloP100

3.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.51

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.26

MVP

0.22

MPC

1.5

ClinPred

0.015

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.088

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over