rs190382829

Positions:

chr7-193451-C-A

Variant summary

Our verdict is Benign. Variant got -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 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

Uncertain significance criteria provided, multiple submitters, no conflicts U:4B:1

Conservation

PhyloP100: 0.564

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 links:

FAM20C (HGNC:):

FAM20C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. 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/exons	MANE	Protein	UniProt
FAM20C	NM_020223.4 linkuse as main transcript	c.252C>A	p.Asn84Lys	missense_variant	1/10	ENST00000313766.6	NP_064608.2	Q8IXL6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM20C	ENST00000313766.6 linkuse as main transcript	c.252C>A	p.Asn84Lys	missense_variant	1/10	1	NM_020223.4	ENSP00000322323.5		Q8IXL6-1
ENSG00000240093	ENST00000467050.1 linkuse as main transcript	n.233+497G>T		intron_variant		4

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

GnomAD3 exomes

AF:

0.0000824

AC:

AN:

97108

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

53978

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 SAS exome

AF:

0.0000566

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

Gnomad4 AFR exome

AF:

0.00696

Gnomad4 AMR exome

AF:

0.000178

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000140

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000581

Gnomad4 OTH exome

AF:

0.000283

GnomAD4 genome

AF:

0.00176

AC:

267

AN:

151432

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

127

AN XY:

74018

show subpopulations

Gnomad4 AFR

AF:

0.00603

Gnomad4 AMR

AF:

0.000789

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000690

Hom.:

Bravo

AF:

0.00194

ExAC

AF:

0.000143

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2017	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

FAM20C-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2019

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

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

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

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