rs36139924

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBS1_Supporting

The NM_020223.4(FAM20C):c.1690A>C(p.Asn564His) variant causes a missense change. The variant allele was found at a frequency of 0.000755 in 1,534,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N564D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00078 ( 0 hom. )

Consequence

FAM20C
NM_020223.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.01

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a region_of_interest Kinase domain (size 211) in uniprot entity FA20C_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_020223.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046839654).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000545 (83/152220) while in subpopulation NFE AF= 0.000956 (65/67996). AF 95% confidence interval is 0.000769. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM20C	NM_020223.4 linkuse as main transcript	c.1690A>C	p.Asn564His	missense_variant	10/10	ENST00000313766.6	NP_064608.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM20C	ENST00000313766.6 linkuse as main transcript	c.1690A>C	p.Asn564His	missense_variant	10/10	1	NM_020223.4	ENSP00000322323	P1	Q8IXL6-1
FAM20C	ENST00000515795.1 linkuse as main transcript	n.1347A>C		non_coding_transcript_exon_variant	7/7	1

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.000956

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000485

AC:

AN:

140220

Hom.:

AF XY:

0.000438

AC XY:

AN XY:

75324

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.000285

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000353

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000858

Gnomad OTH exome

AF:

0.000717

GnomAD4 exome

AF:

0.000778

AC:

1076

AN:

1382210

Hom.:

Cov.:

AF XY:

0.000782

AC XY:

533

AN XY:

681682

show subpopulations

Gnomad4 AFR exome

AF:

0.000158

Gnomad4 AMR exome

AF:

0.000308

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000265

Gnomad4 FIN exome

AF:

0.0000294

Gnomad4 NFE exome

AF:

0.000934

Gnomad4 OTH exome

AF:

0.000554

GnomAD4 genome

AF:

0.000545

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000956

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000744

Hom.:

11384

ExAC

AF:

0.000451

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2022	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 564 of the FAM20C protein (p.Asn564His). This variant is present in population databases (rs36139924, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 935951). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.1690A>C (p.N564H) alteration is located in exon 10 (coding exon 10) of the FAM20C gene. This alteration results from a A to C substitution at nucleotide position 1690, causing the asparagine (N) at amino acid position 564 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Lethal osteosclerotic bone dysplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.12

DEOGEN2

Benign

0.10

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.087

M_CAP

Benign

0.030

MetaRNN

Benign

0.047

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.080

REVEL

Benign

0.19

Sift

Benign

0.55

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.11

MVP

0.13

MPC

0.49

ClinPred

0.011

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.076

gMVP

0.45

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