Genetic Variant FAM20C:p.Gly365Ser (chr7-255869-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_020223.4(FAM20C):c.1093G>A(p.Gly365Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000026 in 1,536,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G365D) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

FAM20C
NM_020223.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.82

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-255870-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1676667.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

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.1093G>A	p.Gly365Ser	missense	Exon 6 of 10	NP_064608.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FAM20C	ENST00000313766.6	TSL:1 MANE Select	c.1093G>A	p.Gly365Ser	missense	Exon 6 of 10	ENSP00000322323.5
FAM20C	ENST00000515795.1	TSL:1	n.750G>A		non_coding_transcript_exon	Exon 3 of 7
FAM20C	ENST00000942064.1		c.1354G>A	p.Gly452Ser	missense	Exon 7 of 11	ENSP00000612123.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1384122

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

682994

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31590

American (AMR)

AF:

0.00

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.00

AC:

AN:

35728

South Asian (SAS)

AF:

0.00

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00000278

AC:

AN:

1078820

Other (OTH)

AF:

0.00

AC:

AN:

57908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.24

PhyloP100

8.8

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.76

Sift

Benign

0.076

Sift4G

Uncertain

0.044

Polyphen

1.0

Vest4

0.87

MutPred

0.86

Gain of catalytic residue at G365 (P = 0.0265)

MVP

0.81

MPC

1.4

ClinPred

0.99

GERP RS

4.9

Varity_R

0.51

gMVP

0.87

Mutation Taster

=17/83

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.46

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.46

Position offset: 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