NM_020223.4:c.1218T>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_020223.4(FAM20C):c.1218T>A(p.Pro406Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,536,036 control chromosomes in the GnomAD database, including 730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 64 hom., cov: 33)

Exomes 𝑓: 0.028 ( 666 hom. )

Consequence

FAM20C
NM_020223.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.50

Publications

1 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

BP6

Variant 7-255994-T-A is Benign according to our data. Variant chr7-255994-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.5 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0262 (3989/152290) while in subpopulation NFE AF = 0.0315 (2142/68012). AF 95% confidence interval is 0.0304. There are 64 homozygotes in GnomAd4. There are 1841 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM20C	NM_020223.4 link	c.1218T>A	p.Pro406Pro	synonymous_variant	Exon 6 of 10	ENST00000313766.6	NP_064608.2	Q8IXL6-1
FAM20C	XR_001744837.2 link	n.*59T>A		downstream_gene_variant
FAM20C	XR_007060116.1 link	n.*59T>A		downstream_gene_variant
FAM20C	XR_007060117.1 link	n.*45T>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM20C	ENST00000313766.6 link	c.1218T>A	p.Pro406Pro	synonymous_variant	Exon 6 of 10	1	NM_020223.4	ENSP00000322323.5	Q8IXL6-1
FAM20C	ENST00000515795.1 link	n.875T>A		non_coding_transcript_exon_variant	Exon 3 of 7	1
FAM20C	ENST00000512382.1 link	n.-201T>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3993

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0285

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0170

Gnomad ASJ

AF:

0.0340

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.0195

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0315

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0225

AC:

3159

AN:

140380

AF XY:

0.0218

show subpopulations

Gnomad AFR exome

AF:

0.0310

Gnomad AMR exome

AF:

0.0151

Gnomad ASJ exome

AF:

0.0341

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0146

Gnomad NFE exome

AF:

0.0330

Gnomad OTH exome

AF:

0.0267

GnomAD4 exome

AF:

0.0285

AC:

39386

AN:

1383746

Hom.:

666

Cov.:

AF XY:

0.0279

AC XY:

19059

AN XY:

682822

show subpopulations

African (AFR)

AF:

0.0299

AC:

945

AN:

31590

American (AMR)

AF:

0.0163

AC:

581

AN:

35688

Ashkenazi Jewish (ASJ)

AF:

0.0345

AC:

868

AN:

25152

East Asian (EAS)

AF:

0.000112

AC:

AN:

35728

South Asian (SAS)

AF:

0.00817

AC:

647

AN:

79230

European-Finnish (FIN)

AF:

0.0171

AC:

583

AN:

34018

Middle Eastern (MID)

AF:

0.0380

AC:

216

AN:

5686

European-Non Finnish (NFE)

AF:

0.0316

AC:

34053

AN:

1078760

Other (OTH)

AF:

0.0257

AC:

1489

AN:

57894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

2497

4993

7490

9986

12483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1274

2548

3822

5096

6370

<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:

0.0262

AC:

3989

AN:

152290

Hom.:

Cov.:

AF XY:

0.0247

AC XY:

1841

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0284

AC:

1182

AN:

41566

American (AMR)

AF:

0.0170

AC:

260

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0340

AC:

118

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00477

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0195

AC:

207

AN:

10616

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0315

AC:

2142

AN:

68012

Other (OTH)

AF:

0.0175

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

202

404

606

808

1010

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0297

Hom.:

Bravo

AF:

0.0269

Asia WGS

AF:

0.00895

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 05, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro406Pro in exon 6 of FAM20C: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 3.57% (215/6028) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs144007479). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

8.0

(source)

DANN

Benign

0.67

PhyloP100

-1.5

Mutation Taster

=99/1

polymorphism (auto)

(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