Variant 2-182838584-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001463.4(FRZB):c.622A>G(p.Thr208Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,612,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

FRZB
NM_001463.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.84

Variant links:

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]

FRZB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.091025025).

BS2

High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FRZB	NM_001463.4 linkuse as main transcript	c.622A>G	p.Thr208Ala	missense_variant	4/6	ENST00000295113.5	NP_001454.2	Q92765D9ZGF6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FRZB	ENST00000295113.5 linkuse as main transcript	c.622A>G	p.Thr208Ala	missense_variant	4/6	1	NM_001463.4	ENSP00000295113.4		Q92765

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250436

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135330

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1460540

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726582

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2024

The c.622A>G (p.T208A) alteration is located in exon 4 (coding exon 4) of the FRZB gene. This alteration results from a A to G substitution at nucleotide position 622, causing the threonine (T) at amino acid position 208 to be replaced by an alanine (A). 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

0.065

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.55

M_CAP

Benign

0.0054

MetaRNN

Benign

0.091

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.72

REVEL

Benign

0.079

Sift

Benign

0.13

Sift4G

Benign

0.19

Polyphen

0.0010

Vest4

0.072

MutPred

0.44

Gain of sheet (P = 0.0827);

MVP

0.45

MPC

0.37

ClinPred

0.087

GERP RS

1.4

Varity_R

0.037

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over