rs148276213

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_020223.4(FAM20C):c.1228T>A(p.Ser410Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00596 in 1,535,878 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 13 hom., cov: 33)

Exomes 𝑓: 0.0060 ( 40 hom. )

Consequence

FAM20C
NM_020223.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:6

Conservation

PhyloP100: 7.07

Publications

11 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: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_020223.4

BP4

Computational evidence support a benign effect (MetaRNN=0.015020758).

BP6

Variant 7-256004-T-A is Benign according to our data. Variant chr7-256004-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 289269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00575 (875/152224) while in subpopulation NFE AF = 0.00653 (444/68010). AF 95% confidence interval is 0.00603. There are 13 homozygotes in GnomAd4. There are 489 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM20C	NM_020223.4 link	c.1228T>A	p.Ser410Thr	missense_variant	Exon 6 of 10	ENST00000313766.6	NP_064608.2	Q8IXL6-1
FAM20C	XR_001744837.2 link	n.*69T>A		downstream_gene_variant
FAM20C	XR_007060116.1 link	n.*69T>A		downstream_gene_variant
FAM20C	XR_007060117.1 link	n.*55T>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM20C	ENST00000313766.6 link	c.1228T>A	p.Ser410Thr	missense_variant	Exon 6 of 10	1	NM_020223.4	ENSP00000322323.5	Q8IXL6-1
FAM20C	ENST00000515795.1 link	n.885T>A		non_coding_transcript_exon_variant	Exon 3 of 7	1
FAM20C	ENST00000512382.1 link	n.-191T>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00576

AC:

876

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0318

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00653

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00481

AC:

674

AN:

140078

AF XY:

0.00492

show subpopulations

Gnomad AFR exome

AF:

0.00134

Gnomad AMR exome

AF:

0.000489

Gnomad ASJ exome

AF:

0.00144

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0346

Gnomad NFE exome

AF:

0.00560

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00598

AC:

8275

AN:

1383654

Hom.:

Cov.:

AF XY:

0.00589

AC XY:

4020

AN XY:

682786

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

31590

American (AMR)

AF:

0.000701

AC:

AN:

35678

Ashkenazi Jewish (ASJ)

AF:

0.00123

AC:

AN:

25140

East Asian (EAS)

AF:

0.00

AC:

AN:

35726

South Asian (SAS)

AF:

0.00490

AC:

388

AN:

79228

European-Finnish (FIN)

AF:

0.0331

AC:

1125

AN:

33998

Middle Eastern (MID)

AF:

0.00106

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00592

AC:

6381

AN:

1078742

Other (OTH)

AF:

0.00492

AC:

285

AN:

57884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

544

1088

1633

2177

2721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

240

480

720

960

1200

<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:

0.00575

AC:

875

AN:

152224

Hom.:

Cov.:

AF XY:

0.00657

AC XY:

489

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41532

American (AMR)

AF:

0.000588

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00477

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0318

AC:

337

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00653

AC:

444

AN:

68010

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00517

Hom.:

Bravo

AF:

0.00305

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00145

AC:

ESP6500EA

AF:

0.00817

AC:

ExAC

AF:

0.00338

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lethal osteosclerotic bone dysplasia

Pathogenic:1Benign:2

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

European Non-Finnish population allele frequency is 0.5092% (rs148276213, 674/140078 alleles, 2 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

Aug 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 17, 2017

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The observed mutation is reported in 1000 Genomes and ExAC databases. The in silico prediction of the mutation is damaging by MutationTaster2 and PROVEAN. The given mutation is probably damaging by Polyphen2 and it is benign by SIFT. The dbSNP reference number of the given mutation is rs148276213. The proband, born of a third degree consanguinity, presented with facial dysmorphism, mild hypotonia and microcephaly. Her CT-scan report showed mild cortical atrophy. Her EEG and karyotype were normal. She was found normal for William syndrome. Her array CGH report showed no quantitative genomic imbalance. She was observed to have chronic constipation, hyperactive behavior, two episodes of seizures, delay in speech, delay in cognitive and motor milestones. Her MRI report showed corpus callosal dysgenesis with absent rostral area. She was also detected with intrauterine growth restriction (IUGR). She was born through Lower segment Cesarian section (LSCS). She presented no neonatal difficulties. Her parents were found to be heterozygous for this allele. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FAM20C: BS1, BS2 -

not specified

Benign:1

Aug 30, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.015

MetaSVM

Uncertain

-0.19

PhyloP100

7.1

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.57

Sift

Benign

0.31

Sift4G

Benign

0.23

Polyphen

0.97

Vest4

0.69

MVP

0.79

MPC

1.2

ClinPred

0.014

GERP RS

4.9

Varity_R

0.42

gMVP

0.89

Mutation Taster

=46/54

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over