19-3523058-C-A

Variant names:

• chr19-3523058-C-A
• rs371487179
• NM_016263.4:c.69C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_016263.4(FZR1):​c.69C>A​(p.Arg23Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R23R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: FZR1 NM_016263.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00001356
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.712
• 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

LOC124904617 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-0.712 with no splicing effect.

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.69C>A	p.Arg23Arg	splice_region synonymous	Exon 2 of 14	NP_057347.2
	FZR1	NM_001136198.1		c.69C>A	p.Arg23Arg	splice_region synonymous	Exon 1 of 13	NP_001129670.1	Q9UM11-1
	FZR1	NM_001136197.1		c.69C>A	p.Arg23Arg	splice_region synonymous	Exon 1 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.69C>A	p.Arg23Arg	splice_region synonymous	Exon 2 of 14	ENSP00000410369.1	Q9UM11-2
	FZR1	ENST00000395095.7	TSL:1	c.69C>A	p.Arg23Arg	splice_region synonymous	Exon 1 of 13	ENSP00000378529.2	Q9UM11-1
	FZR1	ENST00000313639.8	TSL:1	c.69C>A	p.Arg23Arg	splice_region synonymous	Exon 1 of 11	ENSP00000321800.7	Q9UM11-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437702 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 716600

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32984

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091238

Other (OTH) AF: 0.00 AC: 0 AN: 59602

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.11
DANN	Benign	0.85
PhyloP100		-0.71
PromoterAI		-0.023	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0060
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

dbSNP: rs371487179; hg19: chr19-3523056;