7-259915-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020223.4(FAM20C):c.1690A>G(p.Asn564Asp) variant causes a missense change. The variant allele was found at a frequency of 0.458 in 1,534,002 control chromosomes in the GnomAD database, including 164,582 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N564H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.52 ( 21013 hom., cov: 35)

Exomes 𝑓: 0.45 ( 143569 hom. )

Consequence

FAM20C
NM_020223.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B: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: 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.8630966E-6).

BP6

Variant 7-259915-A-G is Benign according to our data. Variant chr7-259915-A-G is described in ClinVar as Benign. ClinVar VariationId is 193731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM20C	NM_020223.4 link	c.1690A>G	p.Asn564Asp	missense_variant	Exon 10 of 10	ENST00000313766.6	NP_064608.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM20C	ENST00000313766.6 link	c.1690A>G	p.Asn564Asp	missense_variant	Exon 10 of 10	1	NM_020223.4	ENSP00000322323.5
FAM20C	ENST00000515795.1 link	n.1347A>G		non_coding_transcript_exon_variant	Exon 7 of 7	1

Frequencies

GnomAD3 genomes

AF:

0.515

AC:

78372

AN:

152054

Hom.:

20974

Cov.:

show subpopulations

Gnomad AFR

AF:

0.666

Gnomad AMI

AF:

0.535

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.462

Gnomad EAS

AF:

0.506

Gnomad SAS

AF:

0.442

Gnomad FIN

AF:

0.554

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.458

Gnomad OTH

AF:

0.498

GnomAD2 exomes

AF:

0.436

AC:

61169

AN:

140220

AF XY:

0.437

show subpopulations

Gnomad AFR exome

AF:

0.672

Gnomad AMR exome

AF:

0.252

Gnomad ASJ exome

AF:

0.458

Gnomad EAS exome

AF:

0.501

Gnomad FIN exome

AF:

0.543

Gnomad NFE exome

AF:

0.457

Gnomad OTH exome

AF:

0.452

GnomAD4 exome

AF:

0.452

AC:

624259

AN:

1381830

Hom.:

143569

Cov.:

AF XY:

0.451

AC XY:

307215

AN XY:

681428

show subpopulations

African (AFR)

AF:

0.671

AC:

21158

AN:

31552

American (AMR)

AF:

0.269

AC:

9608

AN:

35654

Ashkenazi Jewish (ASJ)

AF:

0.462

AC:

11604

AN:

25138

East Asian (EAS)

AF:

0.475

AC:

16945

AN:

35638

South Asian (SAS)

AF:

0.436

AC:

34529

AN:

79136

European-Finnish (FIN)

AF:

0.526

AC:

17888

AN:

34036

Middle Eastern (MID)

AF:

0.486

AC:

2750

AN:

5656

European-Non Finnish (NFE)

AF:

0.448

AC:

482762

AN:

1077236

Other (OTH)

AF:

0.468

AC:

27015

AN:

57784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

20652

41304

61955

82607

103259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14702

29404

44106

58808

73510

<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:

0.516

AC:

78462

AN:

152172

Hom.:

21013

Cov.:

AF XY:

0.516

AC XY:

38407

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.667

AC:

27694

AN:

41526

American (AMR)

AF:

0.371

AC:

5682

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.462

AC:

1601

AN:

3468

East Asian (EAS)

AF:

0.505

AC:

2606

AN:

5158

South Asian (SAS)

AF:

0.443

AC:

2137

AN:

4824

European-Finnish (FIN)

AF:

0.554

AC:

5863

AN:

10590

Middle Eastern (MID)

AF:

0.582

AC:

170

AN:

292

European-Non Finnish (NFE)

AF:

0.458

AC:

31165

AN:

67986

Other (OTH)

AF:

0.500

AC:

1056

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1992

3984

5975

7967

9959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<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:

0.461

Hom.:

20552

Bravo

AF:

0.508

TwinsUK

AF:

0.439

AC:

1626

ALSPAC

AF:

0.430

AC:

1658

ESP6500AA

AF:

0.654

AC:

905

ESP6500EA

AF:

0.443

AC:

1409

ExAC

AF:

0.434

AC:

8679

Asia WGS

AF:

0.498

AC:

1729

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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.Asn564Asp in exon 10 of FAM20C: This variant is not expected to have clinical significance because it has been identified in 72.54% (959/1322) of African chro mosomes by the 1000 Genomes Project (Phase 3; dbSNP rs36139924).

Oct 20, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lethal osteosclerotic bone dysplasia

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.28

DEOGEN2

Benign

0.12

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.052

MetaRNN

Benign

0.0000069

MetaSVM

Benign

-0.91

PhyloP100

4.0

PrimateAI

Benign

0.48

PROVEAN

Benign

0.48

REVEL

Benign

0.17

Sift

Benign

0.94

Sift4G

Benign

0.94

Vest4

0.044

ClinPred

0.0017

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.41

Mutation Taster

=94/6

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