17-68542098-G-T

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.996C>A(p.Asn332Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,613,778 control chromosomes in the GnomAD database, including 76,585 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7512 hom., cov: 32)

Exomes 𝑓: 0.30 ( 69073 hom. )

Consequence

FAM20A
NM_017565.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.59

Publications

48 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
acrodysostosis with multiple hormone resistance
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
Carney complex, type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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=3.4967065E-4).

BP6

Variant 17-68542098-G-T is Benign according to our data. Variant chr17-68542098-G-T is described in ClinVar as Benign. ClinVar VariationId is 260833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM20A	NM_017565.4 link	c.996C>A	p.Asn332Lys	missense_variant	Exon 7 of 11	ENST00000592554.2	NP_060035.2	Q96MK3L8B8N7Q8IYA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM20A	ENST00000592554.2 link	c.996C>A	p.Asn332Lys	missense_variant	Exon 7 of 11	1	NM_017565.4	ENSP00000468308.1		Q96MK3

Frequencies

GnomAD3 genomes

AF:

0.308

AC:

46716

AN:

151896

Hom.:

7501

Cov.:

show subpopulations

Gnomad AFR

AF:

0.268

Gnomad AMI

AF:

0.361

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.554

Gnomad SAS

AF:

0.271

Gnomad FIN

AF:

0.320

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.337

GnomAD2 exomes

AF:

0.332

AC:

83294

AN:

251242

AF XY:

0.325

show subpopulations

Gnomad AFR exome

AF:

0.258

Gnomad AMR exome

AF:

0.443

Gnomad ASJ exome

AF:

0.262

Gnomad EAS exome

AF:

0.577

Gnomad FIN exome

AF:

0.322

Gnomad NFE exome

AF:

0.291

Gnomad OTH exome

AF:

0.328

GnomAD4 exome

AF:

0.304

AC:

443759

AN:

1461766

Hom.:

69073

Cov.:

AF XY:

0.302

AC XY:

219440

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.267

AC:

8940

AN:

33480

American (AMR)

AF:

0.431

AC:

19291

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.265

AC:

6925

AN:

26136

East Asian (EAS)

AF:

0.534

AC:

21215

AN:

39700

South Asian (SAS)

AF:

0.284

AC:

24489

AN:

86258

European-Finnish (FIN)

AF:

0.324

AC:

17302

AN:

53358

Middle Eastern (MID)

AF:

0.329

AC:

1900

AN:

5768

European-Non Finnish (NFE)

AF:

0.292

AC:

324969

AN:

1111962

Other (OTH)

AF:

0.310

AC:

18728

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

17933

35865

53798

71730

89663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11016

22032

33048

44064

55080

<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:

0.308

AC:

46763

AN:

152012

Hom.:

7512

Cov.:

AF XY:

0.311

AC XY:

23136

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.268

AC:

11096

AN:

41450

American (AMR)

AF:

0.404

AC:

6179

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

886

AN:

3468

East Asian (EAS)

AF:

0.556

AC:

2866

AN:

5152

South Asian (SAS)

AF:

0.270

AC:

1302

AN:

4814

European-Finnish (FIN)

AF:

0.320

AC:

3390

AN:

10582

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.293

AC:

19893

AN:

67942

Other (OTH)

AF:

0.339

AC:

715

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1643

3286

4928

6571

8214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

454

908

1362

1816

2270

<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:

0.298

Hom.:

30211

Bravo

AF:

0.313

TwinsUK

AF:

0.289

AC:

1072

ALSPAC

AF:

0.302

AC:

1162

ESP6500AA

AF:

0.274

AC:

1208

ESP6500EA

AF:

0.303

AC:

2606

ExAC

AF:

0.324

AC:

39275

Asia WGS

AF:

0.385

AC:

1340

AN:

3478

EpiCase

AF:

0.292

EpiControl

AF:

0.297

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amelogenesis imperfecta type 1G

Benign:1

Aug 10, 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

0.16

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.70

MetaRNN

Benign

0.00035

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

PhyloP100

2.6

PrimateAI

Uncertain

0.48

Sift4G

Benign

1.0

Polyphen

0.81

Vest4

0.089

MutPred

0.29

Gain of ubiquitination at N332 (P = 0.0211);

MPC

0.53

ClinPred

0.0083

GERP RS

5.0

Varity_R

0.21

gMVP

0.67

Mutation Taster

=76/24

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