chr7-259915-A-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_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. 14/21 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:5

Conservation

PhyloP100: 4.01

Publications

26 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

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 the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1690A>C	p.Asn564His	missense	Exon 10 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.1690A>C	p.Asn564His	missense	Exon 10 of 10	ENSP00000322323.5	Q8IXL6-1
FAM20C	ENST00000515795.1	TSL:1	n.1347A>C		non_coding_transcript_exon	Exon 7 of 7
FAM20C	ENST00000942064.1		c.1951A>C	p.Asn651His	missense	Exon 11 of 11	ENSP00000612123.1

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

GnomAD2 exomes

AF:

0.000485

AC:

AN:

140220

AF XY:

0.000438

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 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

African (AFR)

AF:

0.000158

AC:

AN:

31558

American (AMR)

AF:

0.000308

AC:

AN:

35672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25154

East Asian (EAS)

AF:

0.00

AC:

AN:

35662

South Asian (SAS)

AF:

0.000265

AC:

AN:

79174

European-Finnish (FIN)

AF:

0.0000294

AC:

AN:

34046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.000934

AC:

1006

AN:

1077476

Other (OTH)

AF:

0.000554

AC:

AN:

57802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

126

168

210

<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:

0.000545

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41544

American (AMR)

AF:

0.000719

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000956

AC:

AN:

67996

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000428

Hom.:

20552

ExAC

AF:

0.000451

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lethal osteosclerotic bone dysplasia (2)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

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

PhyloP100

4.0

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

Mutation Taster

=93/7

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over