2-182838419-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001463.4(FRZB):c.787G>A(p.Glu263Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000436 in 1,610,204 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (3 hom.)
• Consequence: FRZB NM_001463.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04776901).
• BS2: High AC in GnomAd at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRZB	NM_001463.4	c.787G>A	p.Glu263Lys	missense_variant	4/6	ENST00000295113.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRZB	ENST00000295113.5	c.787G>A	p.Glu263Lys	missense_variant	4/6	1	NM_001463.4	P1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 151942 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000723

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000571 AC: 143 AN: 250454 Hom.: 1 AF XY: 0.000665 AC XY: 90 AN XY: 135354

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000734

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000428 AC: 624 AN: 1458144 Hom.: 3 Cov.: 31 AF XY: 0.000455 AC XY: 330 AN XY: 725642

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00303

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000368

Gnomad4 OTH exome AF: 0.000647

GnomAD4 genome AF: 0.000513 AC: 78 AN: 152060 Hom.: 1 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74330

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000722

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000501

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000651 AC: 79

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000983

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.787G>A (p.E263K) alteration is located in exon 4 (coding exon 4) of the FRZB gene. This alteration results from a G to A substitution at nucleotide position 787, causing the glutamic acid (E) at amino acid position 263 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.16
Sift	Benign	0.78	T
Sift4G	Benign	1.0	T
Polyphen		0.65	P
Vest4		0.74
MVP		0.67
MPC		1.0
ClinPred		0.13	T
GERP RS		5.1
Varity_R		0.37
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs138147194; hg19: chr2-183703147;