chr17-68537514-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_017565.4(FAM20A):c.1589T>C(p.Leu530Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,613,080 control chromosomes in the GnomAD database, including 379,606 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.73 ( 40888 hom., cov: 30)

Exomes 𝑓: 0.68 ( 338718 hom. )

Consequence

FAM20A
NM_017565.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.172

Publications

32 publications found

Variant links:

Genes affected

FAM20A (HGNC:23015): (FAM20A golgi associated secretory pathway pseudokinase) This locus encodes a protein that is likely secreted and may function in hematopoiesis. A mutation at this locus has been associated with amelogenesis imperfecta and gingival hyperplasia syndrome. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Aug 2011]

FAM20A links:

PRKAR1A (HGNC:9388): (protein kinase cAMP-dependent type I regulatory subunit alpha) cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. This gene encodes one of the regulatory subunits. This protein was found to be a tissue-specific extinguisher that down-regulates the expression of seven liver genes in hepatoma x fibroblast hybrids. Mutations in this gene cause Carney complex (CNC). This gene can fuse to the RET protooncogene by gene rearrangement and form the thyroid tumor-specific chimeric oncogene known as PTC2. A nonconventional nuclear localization sequence (NLS) has been found for this protein which suggests a role in DNA replication via the protein serving as a nuclear transport protein for the second subunit of the Replication Factor C (RFC40). Several alternatively spliced transcript variants encoding two different isoforms have been observed. [provided by RefSeq, Jan 2013]

PRKAR1A Gene-Disease associations (from GenCC):

Acrodysostosis 1 with or without hormone resistance
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
acrodysostosis with multiple hormone resistance
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
Carney complex, type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
pigmented nodular adrenocortical disease, primary, 1
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
acrodysostosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Carney complex
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial atrial myxoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
primary pigmented nodular adrenocortical disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRKAR1A 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=8.659668E-7).

BP6

Variant 17-68537514-A-G is Benign according to our data. Variant chr17-68537514-A-G is described in ClinVar as Benign. ClinVar VariationId is 260830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017565.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM20A	NM_017565.4	MANE Select	c.1589T>C	p.Leu530Ser	missense	Exon 11 of 11	NP_060035.2	Q96MK3
FAM20A	NM_001243746.2		c.1175T>C	p.Leu392Ser	missense	Exon 12 of 12	NP_001230675.1
PRKAR1A	NM_001276290.1		c.973+7513A>G		intron	N/A	NP_001263219.1	P10644-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAM20A	ENST00000592554.2	TSL:1 MANE Select	c.1589T>C	p.Leu530Ser	missense	Exon 11 of 11	ENSP00000468308.1	Q96MK3
FAM20A	ENST00000226094.9	TSL:1	n.1267T>C		non_coding_transcript_exon	Exon 11 of 11
FAM20A	ENST00000882126.1		c.1619T>C	p.Leu540Ser	missense	Exon 12 of 12	ENSP00000552185.1

Frequencies

GnomAD3 genomes

AF:

0.728

AC:

110611

AN:

151854

Hom.:

40853

Cov.:

show subpopulations

Gnomad AFR

AF:

0.837

Gnomad AMI

AF:

0.655

Gnomad AMR

AF:

0.758

Gnomad ASJ

AF:

0.575

Gnomad EAS

AF:

0.901

Gnomad SAS

AF:

0.733

Gnomad FIN

AF:

0.694

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.656

Gnomad OTH

AF:

0.733

GnomAD2 exomes

AF:

0.714

AC:

178453

AN:

249942

AF XY:

0.709

show subpopulations

Gnomad AFR exome

AF:

0.842

Gnomad AMR exome

AF:

0.784

Gnomad ASJ exome

AF:

0.584

Gnomad EAS exome

AF:

0.903

Gnomad FIN exome

AF:

0.692

Gnomad NFE exome

AF:

0.652

Gnomad OTH exome

AF:

0.688

GnomAD4 exome

AF:

0.678

AC:

990889

AN:

1461108

Hom.:

338718

Cov.:

AF XY:

0.679

AC XY:

493511

AN XY:

726772

show subpopulations

African (AFR)

AF:

0.843

AC:

28208

AN:

33468

American (AMR)

AF:

0.779

AC:

34753

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.580

AC:

15147

AN:

26124

East Asian (EAS)

AF:

0.925

AC:

36689

AN:

39682

South Asian (SAS)

AF:

0.748

AC:

64403

AN:

86138

European-Finnish (FIN)

AF:

0.689

AC:

36764

AN:

53368

Middle Eastern (MID)

AF:

0.708

AC:

4086

AN:

5768

European-Non Finnish (NFE)

AF:

0.656

AC:

729298

AN:

1111568

Other (OTH)

AF:

0.688

AC:

41541

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

19217

38434

57652

76869

96086

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19220

38440

57660

76880

96100

<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:

0.728

AC:

110704

AN:

151972

Hom.:

40888

Cov.:

AF XY:

0.731

AC XY:

54309

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.837

AC:

34719

AN:

41472

American (AMR)

AF:

0.758

AC:

11572

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.575

AC:

1996

AN:

3470

East Asian (EAS)

AF:

0.901

AC:

4632

AN:

5142

South Asian (SAS)

AF:

0.734

AC:

3523

AN:

4802

European-Finnish (FIN)

AF:

0.694

AC:

7329

AN:

10568

Middle Eastern (MID)

AF:

0.690

AC:

203

AN:

294

European-Non Finnish (NFE)

AF:

0.656

AC:

44592

AN:

67936

Other (OTH)

AF:

0.730

AC:

1542

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1481

2962

4444

5925

7406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

830

1660

2490

3320

4150

<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:

0.683

Hom.:

147623

Bravo

AF:

0.740

TwinsUK

AF:

0.660

AC:

2446

ALSPAC

AF:

0.658

AC:

2536

ESP6500AA

AF:

0.832

AC:

3667

ESP6500EA

AF:

0.662

AC:

5694

ExAC

AF:

0.711

AC:

86297

Asia WGS

AF:

0.806

AC:

2803

AN:

3478

EpiCase

AF:

0.655

EpiControl

AF:

0.661

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Amelogenesis imperfecta type 1G (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

2.2

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.0056

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.073

MetaRNN

Benign

8.7e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.51

PhyloP100

0.17

PrimateAI

Benign

0.29

Sift4G

Benign

0.82

Polyphen

0.0

Vest4

0.010

MPC

0.22

ClinPred

0.0024

GERP RS

1.1

Varity_R

0.020

gMVP

0.24

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over