Genetic Variant NM_020223.4:c.145G>A (chr7-193344-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020223.4(FAM20C):c.145G>A(p.Ala49Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A49A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FAM20C
NM_020223.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.529

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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

FAM20C links:

ENSG00000240093 (HGNC:):

ENSG00000240093 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24909955).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020223.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20C	NM_020223.4	MANE Select	c.145G>A	p.Ala49Thr	missense	Exon 1 of 10	NP_064608.2	Q8IXL6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM20C	ENST00000313766.6	TSL:1 MANE Select	c.145G>A	p.Ala49Thr	missense	Exon 1 of 10	ENSP00000322323.5	Q8IXL6-1
FAM20C	ENST00000942064.1		c.145G>A	p.Ala49Thr	missense	Exon 1 of 11	ENSP00000612123.1
FAM20C	ENST00000866115.1		c.145G>A	p.Ala49Thr	missense	Exon 1 of 11	ENSP00000536174.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1155536

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

565036

African (AFR)

AF:

0.00

AC:

AN:

22724

American (AMR)

AF:

0.00

AC:

AN:

13370

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16176

East Asian (EAS)

AF:

0.00

AC:

AN:

22728

South Asian (SAS)

AF:

0.00

AC:

AN:

47092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3638

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

956714

Other (OTH)

AF:

0.00

AC:

AN:

44916

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0038

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.25

MetaSVM

Uncertain

-0.10

PhyloP100

-0.53

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.99

REVEL

Benign

0.16

Sift

Uncertain

0.018

Sift4G

Benign

0.28

Polyphen

0.48

Vest4

0.037

MutPred

0.18

Gain of glycosylation at A49 (P = 0.0148)

MVP

0.25

MPC

0.46

ClinPred

0.29

GERP RS

2.1

Varity_R

0.053

gMVP

0.45

Mutation Taster

=89/11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over