2-182834955-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001463.4(FRZB):c.872T>C(p.Met291Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0068 in 1,609,976 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (43 hom.)
• Consequence: FRZB NM_001463.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.54

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006691307).
• BP6: Variant 2-182834955-A-G is Benign according to our data. Variant chr2-182834955-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 774293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 877 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRZB	NM_001463.4	c.872T>C	p.Met291Thr	missense_variant	6/6	ENST00000295113.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRZB	ENST00000295113.5	c.872T>C	p.Met291Thr	missense_variant	6/6	1	NM_001463.4	P1

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 877 AN: 152106 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00564

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00816

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00626 AC: 1571 AN: 250764 Hom.: 6 AF XY: 0.00607 AC XY: 823 AN XY: 135524

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00624

Gnomad ASJ exome AF: 0.0183

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00518

Gnomad NFE exome AF: 0.00884

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.00691 AC: 10069 AN: 1457752 Hom.: 43 Cov.: 29 AF XY: 0.00666 AC XY: 4834 AN XY: 725450

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00594

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00558

Gnomad4 NFE exome AF: 0.00773

Gnomad4 OTH exome AF: 0.00674

GnomAD4 genome AF: 0.00576 AC: 877 AN: 152224 Hom.: 4 Cov.: 32 AF XY: 0.00531 AC XY: 395 AN XY: 74414

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00563

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00816

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00741 Hom.: 3

Bravo AF: 0.00581

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00628 AC: 762

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00819

EpiControl AF: 0.00806

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	FRZB: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	18
Dann	Benign	0.90
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.93	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.076
Sift	Benign	0.32	T
Sift4G	Benign	0.20	T
Polyphen		0.018	B
Vest4		0.090
MVP		0.90
MPC		0.55
ClinPred		0.024	T
GERP RS		4.4
Varity_R		0.12
gMVP		0.28

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: rs112094045; hg19: chr2-183699682; COSMIC: COSV99039305;