2-182834857-G-C

Variant names:

• chr2-182834857-G-C
• rs7775
• NM_001463.4:c.970C>G

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.970C>G​(p.Arg324Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0858 in 1,610,096 control chromosomes in the GnomAD database, including 8,175 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R324H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (2120 hom., cov: 32)
  • Exomes 𝑓: 0.081 (6055 hom.)
• Consequence: FRZB NM_001463.4 missense
• Clinical Significance: Benign; risk factor no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 3.92
• Publications: 80 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=0.0013847649).
• BP6: Variant 2-182834857-G-C is Benign according to our data. Variant chr2-182834857-G-C is described in ClinVar as Benign|risk_factor. ClinVar VariationId is 5220.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRZB	NM_001463.4	c.970C>G	p.Arg324Gly	missense_variant	Exon 6 of 6	ENST00000295113.5	NP_001454.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRZB	ENST00000295113.5	c.970C>G	p.Arg324Gly	missense_variant	Exon 6 of 6	1	NM_001463.4	ENSP00000295113.4

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20160 AN: 151988 Hom.: 2119 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0903

Gnomad ASJ AF: 0.0982

Gnomad EAS AF: 0.00984

Gnomad SAS AF: 0.0597

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.0826

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.0801 AC: 20106 AN: 250924 AF XY: 0.0765

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.0607

Gnomad ASJ exome AF: 0.0927

Gnomad EAS exome AF: 0.00756

Gnomad FIN exome AF: 0.0259

Gnomad NFE exome AF: 0.0822

Gnomad OTH exome AF: 0.0922

GnomAD4 exome AF: 0.0809 AC: 117951 AN: 1457990 Hom.: 6055 Cov.: 30 AF XY: 0.0794 AC XY: 57582 AN XY: 725508

African (AFR) AF: 0.292 AC: 9735 AN: 33340

American (AMR) AF: 0.0651 AC: 2906 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0936 AC: 2442 AN: 26100

East Asian (EAS) AF: 0.00491 AC: 195 AN: 39682

South Asian (SAS) AF: 0.0573 AC: 4942 AN: 86196

European-Finnish (FIN) AF: 0.0276 AC: 1472 AN: 53384

Middle Eastern (MID) AF: 0.125 AC: 723 AN: 5762

European-Non Finnish (NFE) AF: 0.0814 AC: 90212 AN: 1108668

Other (OTH) AF: 0.0884 AC: 5324 AN: 60208

GnomAD4 genome AF: 0.133 AC: 20184 AN: 152106 Hom.: 2120 Cov.: 32 AF XY: 0.127 AC XY: 9465 AN XY: 74362

African (AFR) AF: 0.288 AC: 11949 AN: 41458

American (AMR) AF: 0.0901 AC: 1376 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0982 AC: 341 AN: 3472

East Asian (EAS) AF: 0.00948 AC: 49 AN: 5170

South Asian (SAS) AF: 0.0595 AC: 287 AN: 4820

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10606

Middle Eastern (MID) AF: 0.151 AC: 44 AN: 292

European-Non Finnish (NFE) AF: 0.0826 AC: 5614 AN: 67996

Other (OTH) AF: 0.134 AC: 283 AN: 2108

Alfa AF: 0.0461 Hom.: 72

Bravo AF: 0.145

TwinsUK AF: 0.0763 AC: 283

ALSPAC AF: 0.0823 AC: 317

ESP6500AA AF: 0.284 AC: 1250

ESP6500EA AF: 0.0880 AC: 757

ExAC AF: 0.0858 AC: 10413

Asia WGS AF: 0.0680 AC: 239 AN: 3478

EpiCase AF: 0.0918

EpiControl AF: 0.0946

ClinVar

Significance: Benign; risk factor

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

FRZB-related disorder Benign:1

Dec 03, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Osteoarthritis susceptibility 1 Other:1

Jun 29, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.24
Sift	Uncertain	0.012	D
Sift4G	Benign	0.099	T
Vest4		0.051
ClinPred		0.014	T
GERP RS		3.6
Varity_R		0.12
gMVP		0.47
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7775; hg19: chr2-183699584; COSMIC: COSV54553092;