Genetic Variant FZR1:p.Asn143Asn (chr19-3527021-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_016263.4(FZR1):c.429C>T(p.Asn143Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00675 in 1,612,654 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0044 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0070 ( 51 hom. )

Consequence

FZR1
NM_016263.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.72

Publications

1 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 19-3527021-C-T is Benign according to our data. Variant chr19-3527021-C-T is described in ClinVar as Benign. ClinVar VariationId is 2648988.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.72 with no splicing effect.

BS2

High AC in GnomAd4 at 663 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.429C>T	p.Asn143Asn	synonymous	Exon 6 of 14	NP_057347.2
FZR1	NM_001136198.1		c.429C>T	p.Asn143Asn	synonymous	Exon 5 of 13	NP_001129670.1	Q9UM11-1
FZR1	NM_001136197.1		c.387+635C>T		intron	N/A	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.429C>T	p.Asn143Asn	synonymous	Exon 6 of 14	ENSP00000410369.1	Q9UM11-2
FZR1	ENST00000395095.7	TSL:1	c.429C>T	p.Asn143Asn	synonymous	Exon 5 of 13	ENSP00000378529.2	Q9UM11-1
FZR1	ENST00000313639.8	TSL:1	c.387+635C>T		intron	N/A	ENSP00000321800.7	Q9UM11-3

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

661

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00930

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00701

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00502

AC:

1258

AN:

250368

AF XY:

0.00560

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00570

Gnomad ASJ exome

AF:

0.000399

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000883

Gnomad NFE exome

AF:

0.00613

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00700

AC:

10224

AN:

1460350

Hom.:

Cov.:

AF XY:

0.00706

AC XY:

5130

AN XY:

726540

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33472

American (AMR)

AF:

0.00541

AC:

242

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0105

AC:

907

AN:

86256

European-Finnish (FIN)

AF:

0.000859

AC:

AN:

52378

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00764

AC:

8496

AN:

1111576

Other (OTH)

AF:

0.00795

AC:

480

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

501

1002

1504

2005

2506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

318

636

954

1272

1590

<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:

0.00435

AC:

663

AN:

152304

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

322

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41564

American (AMR)

AF:

0.00503

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00972

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00701

AC:

477

AN:

68000

Other (OTH)

AF:

0.00474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00513

Hom.:

Bravo

AF:

0.00513

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00851

EpiControl

AF:

0.00504

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

4.5

(source)

DANN

Benign

0.51

PhyloP100

-2.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: 33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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