Genetic Variant FAM20C:p.Ala49Ala (chr7-193346-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_020223.4(FAM20C):c.147G>A(p.Ala49Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 149,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000061 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FAM20C
NM_020223.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.19

Publications

0 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:

ENSG00000240093 (HGNC:):

ENSG00000240093 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 7-193346-G-A is Benign according to our data. Variant chr7-193346-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2085256.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.19 with no splicing effect.

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.147G>A	p.Ala49Ala	synonymous	Exon 1 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.147G>A	p.Ala49Ala	synonymous	Exon 1 of 10	ENSP00000322323.5	Q8IXL6-1
FAM20C	ENST00000942064.1		c.147G>A	p.Ala49Ala	synonymous	Exon 1 of 11	ENSP00000612123.1
FAM20C	ENST00000866115.1		c.147G>A	p.Ala49Ala	synonymous	Exon 1 of 11	ENSP00000536174.1

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

149868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

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:

0.000488

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000614

AC:

AN:

1140258

Hom.:

Cov.:

AF XY:

0.00000899

AC XY:

AN XY:

556028

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22322

American (AMR)

AF:

0.00

AC:

AN:

11538

Ashkenazi Jewish (ASJ)

AF:

0.0000654

AC:

AN:

15296

East Asian (EAS)

AF:

0.00

AC:

AN:

22670

South Asian (SAS)

AF:

0.0000465

AC:

AN:

42976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3532

European-Non Finnish (NFE)

AF:

0.00000421

AC:

AN:

950072

Other (OTH)

AF:

0.00

AC:

AN:

44300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000200

AC:

AN:

149868

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

73072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41152

American (AMR)

AF:

0.000133

AC:

AN:

15068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67296

Other (OTH)

AF:

0.000488

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

8.6

(source)

DANN

Benign

0.94

PhyloP100

-2.2

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