rs288326

Variant names:

• chr2-182838608-G-A
• rs288326
• NM_001463.4:c.598C>T
• FRZB p.Arg200Trp

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001463.4(FRZB):​c.598C>T​(p.Arg200Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,609,516 control chromosomes in the GnomAD database, including 9,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (no stars). Synonymous variant affecting the same amino acid position (i.e. R200R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.082 (755 hom., cov: 32)
  • Exomes 𝑓: 0.10 (9041 hom.)
• Consequence: FRZB NM_001463.4 missense
• Clinical Significance: Benign; risk factor no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 2.31
• Publications: 79 publications found

Genes affected

FRZB (HGNC:3959): (frizzled related protein) The protein encoded by this gene is a secreted protein that is involved in the regulation of bone development. Defects in this gene are a cause of female-specific osteoarthritis (OA) susceptibility. [provided by RefSeq, Apr 2010]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022199154).
• BP6: Variant 2-182838608-G-A is Benign according to our data. Variant chr2-182838608-G-A is described in ClinVar as Benign|risk_factor. ClinVar VariationId is 5221.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001463.4. 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
	FRZB	NM_001463.4	MANE Select	c.598C>T	p.Arg200Trp	missense	Exon 4 of 6	NP_001454.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRZB	ENST00000295113.5	TSL:1 MANE Select	c.598C>T	p.Arg200Trp	missense	Exon 4 of 6	ENSP00000295113.4	Q92765
	FRZB	ENST00000957773.1		c.598C>T	p.Arg200Trp	missense	Exon 4 of 7	ENSP00000627832.1
	FRZB	ENST00000888346.1		c.550C>T	p.Arg184Trp	missense	Exon 3 of 5	ENSP00000558405.1

Frequencies

GnomAD3 genomes AF: 0.0818 AC: 12411 AN: 151750 Hom.: 755 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.0847

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0886

GnomAD2 exomes AF: 0.0818 AC: 20449 AN: 249838 AF XY: 0.0840

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.0564

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0520

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.0928

GnomAD4 exome AF: 0.104 AC: 151565 AN: 1457648 Hom.: 9041 Cov.: 31 AF XY: 0.103 AC XY: 74509 AN XY: 725312

African (AFR) AF: 0.0248 AC: 827 AN: 33368

American (AMR) AF: 0.0585 AC: 2612 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 4140 AN: 26016

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39662

South Asian (SAS) AF: 0.0392 AC: 3382 AN: 86178

European-Finnish (FIN) AF: 0.0569 AC: 3035 AN: 53378

Middle Eastern (MID) AF: 0.0922 AC: 529 AN: 5740

European-Non Finnish (NFE) AF: 0.118 AC: 131281 AN: 1108472

Other (OTH) AF: 0.0956 AC: 5752 AN: 60196

GnomAD4 genome AF: 0.0817 AC: 12405 AN: 151868 Hom.: 755 Cov.: 32 AF XY: 0.0783 AC XY: 5811 AN XY: 74218

African (AFR) AF: 0.0305 AC: 1264 AN: 41440

American (AMR) AF: 0.0845 AC: 1287 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 558 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0330 AC: 159 AN: 4812

European-Finnish (FIN) AF: 0.0513 AC: 542 AN: 10568

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8026 AN: 67880

Other (OTH) AF: 0.0877 AC: 185 AN: 2110

Alfa AF: 0.106 Hom.: 3540

Bravo AF: 0.0828

Asia WGS AF: 0.0200 AC: 72 AN: 3478

EpiCase AF: 0.124

EpiControl AF: 0.123

ClinVar

ClinVar submissions

Significance: Benign; risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	FRZB-related disorder (1)
-	-	-	Osteoarthritis susceptibility 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Varity_R		0.40
gMVP		0.81
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs288326;

hg19: chr2-183703336;

COSMIC: COSV107327929;