rs190382829

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_020223.4(FAM20C):c.252C>A(p.Asn84Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,462,000 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N84S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

FAM20C
NM_020223.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.564

Publications

0 publications found

Variant links:

Genes affected

FAM20C (HGNC:22140): (FAM20C golgi associated secretory pathway kinase) This gene encodes a member of the family of secreted protein kinases. The encoded protein binds calcium and phosphorylates proteins involved in bone mineralization. Mutations in this gene are associated with the autosomal recessive disorder Raine syndrome. [provided by RefSeq, Apr 2014]

FAM20C Gene-Disease associations (from GenCC):

lethal osteosclerotic bone dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

FAM20C links:

ENSG00000240093 (HGNC:):

ENSG00000240093 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005661905).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00176 (267/151432) while in subpopulation AFR AF = 0.00603 (250/41484). AF 95% confidence interval is 0.00541. There are 2 homozygotes in GnomAd4. There are 127 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM20C	NM_020223.4 link	c.252C>A	p.Asn84Lys	missense_variant	Exon 1 of 10	ENST00000313766.6	NP_064608.2	Q8IXL6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM20C	ENST00000313766.6 link	c.252C>A	p.Asn84Lys	missense_variant	Exon 1 of 10	1	NM_020223.4	ENSP00000322323.5		Q8IXL6-1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

267

AN:

151324

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000790

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.0000824

AC:

AN:

97108

AF XY:

0.0000741

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.0000570

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000160

AC:

210

AN:

1310568

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

AN XY:

646160

show subpopulations

African (AFR)

AF:

0.00696

AC:

183

AN:

26300

American (AMR)

AF:

0.000178

AC:

AN:

28060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22148

East Asian (EAS)

AF:

0.00

AC:

AN:

27082

South Asian (SAS)

AF:

0.0000140

AC:

AN:

71192

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4934

European-Non Finnish (NFE)

AF:

0.00000581

AC:

AN:

1031898

Other (OTH)

AF:

0.000283

AC:

AN:

52996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00176

AC:

267

AN:

151432

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

127

AN XY:

74018

show subpopulations

African (AFR)

AF:

0.00603

AC:

250

AN:

41484

American (AMR)

AF:

0.000789

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000195

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67758

Other (OTH)

AF:

0.00143

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000690

Hom.:

Bravo

AF:

0.00194

ExAC

AF:

0.000143

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jun 04, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 84 of the FAM20C protein (p.Asn84Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with FAM20C-related conditions. ClinVar contains an entry for this variant (Variation ID: 235432). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Oct 09, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

FAM20C-related disorder

Benign:1

Jul 29, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0083

Eigen

Benign

0.048

Eigen_PC

Benign

0.094

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.0057

MetaSVM

Benign

-0.36

PhyloP100

0.56

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.29

Sift

Benign

0.071

Sift4G

Benign

0.12

Polyphen

0.61

Vest4

0.23

MutPred

0.25

Gain of ubiquitination at N84 (P = 0.0128);

MVP

0.41

MPC

0.55

ClinPred

0.057

GERP RS

3.6

Varity_R

0.27

gMVP

0.49

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over