NM_016263.4:c.559G>A

Variant names:

• chr19-3527719-G-A
• NM_016263.4:c.559G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_016263.4(FZR1):​c.559G>A​(p.Asp187Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D187G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FZR1 NM_016263.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.70
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-3527720-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1802183.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• PP5: Variant 19-3527719-G-A is Pathogenic according to our data. Variant chr19-3527719-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1802184.Status of the report is no_assertion_criteria_provided, 0 stars.

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.559G>A	p.Asp187Asn	missense	Exon 7 of 14	NP_057347.2
	FZR1	NM_001136198.1		c.559G>A	p.Asp187Asn	missense	Exon 6 of 13	NP_001129670.1	Q9UM11-1
	FZR1	NM_001136197.1		c.387+1333G>A		intron	N/A	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.559G>A	p.Asp187Asn	missense	Exon 7 of 14	ENSP00000410369.1	Q9UM11-2
	FZR1	ENST00000395095.7	TSL:1	c.559G>A	p.Asp187Asn	missense	Exon 6 of 13	ENSP00000378529.2	Q9UM11-1
	FZR1	ENST00000313639.8	TSL:1	c.387+1333G>A		intron	N/A	ENSP00000321800.7	Q9UM11-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy 109 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.86	T
PhyloP100		9.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.60		Loss of phosphorylation at Y189 (P = 0.0739)
MVP		0.68
MPC		2.0
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.81
gMVP		0.36
Mutation Taster		=34/66	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: chr19-3527717;