19-3530796-C-T

Variant names:

• chr19-3530796-C-T
• NM_016263.4:c.659C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_016263.4(FZR1):​c.659C>T​(p.Thr220Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. T220T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FZR1 NM_016263.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.59
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZR1	NM_016263.4	MANE Select	c.659C>T	p.Thr220Met	missense	Exon 8 of 14	NP_057347.2
	FZR1	NM_001136198.1		c.659C>T	p.Thr220Met	missense	Exon 7 of 13	NP_001129670.1	Q9UM11-1
	FZR1	NM_001136197.1		c.392C>T	p.Thr131Met	missense	Exon 5 of 11	NP_001129669.1	Q9UM11-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZR1	ENST00000441788.7	TSL:1 MANE Select	c.659C>T	p.Thr220Met	missense	Exon 8 of 14	ENSP00000410369.1	Q9UM11-2
	FZR1	ENST00000395095.7	TSL:1	c.659C>T	p.Thr220Met	missense	Exon 7 of 13	ENSP00000378529.2	Q9UM11-1
	FZR1	ENST00000313639.8	TSL:1	c.392C>T	p.Thr131Met	missense	Exon 5 of 11	ENSP00000321800.7	Q9UM11-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	FZR1-related condition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	-0.26	T
PhyloP100		7.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.33		Gain of sheet (P = 0.1208)
MVP		0.54
MPC		2.6
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.61
gMVP		0.35
Mutation Taster		=43/57	disease causing

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

Other links and lift over

hg19: chr19-3530794; COSMIC: COSV58051142; COSMIC: COSV58051142;