chr17-68537514-A-G

Position:

chr17-68537514-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 260830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-68537514-A-G is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM20A	NM_017565.4 linkuse as main transcript	c.1589T>C	p.Leu530Ser	missense_variant	11/11	ENST00000592554.2	NP_060035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM20A	ENST00000592554.2 linkuse as main transcript	c.1589T>C	p.Leu530Ser	missense_variant	11/11	1	NM_017565.4	ENSP00000468308	P1

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

GnomAD3 exomes

AF:

0.714

AC:

178453

AN:

249942

Hom.:

64632

AF XY:

0.709

AC XY:

95761

AN XY:

135054

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 SAS exome

AF:

0.747

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

Gnomad4 AFR exome

AF:

0.843

Gnomad4 AMR exome

AF:

0.779

Gnomad4 ASJ exome

AF:

0.580

Gnomad4 EAS exome

AF:

0.925

Gnomad4 SAS exome

AF:

0.748

Gnomad4 FIN exome

AF:

0.689

Gnomad4 NFE exome

AF:

0.656

Gnomad4 OTH exome

AF:

0.688

GnomAD4 genome

AF:

0.728

AC:

110704

AN:

151972

Hom.:

40888

Cov.:

AF XY:

0.731

AC XY:

54309

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.837

Gnomad4 AMR

AF:

0.758

Gnomad4 ASJ

AF:

0.575

Gnomad4 EAS

AF:

0.901

Gnomad4 SAS

AF:

0.734

Gnomad4 FIN

AF:

0.694

Gnomad4 NFE

AF:

0.656

Gnomad4 OTH

AF:

0.730

Alfa

AF:

0.676

Hom.:

74236

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Amelogenesis imperfecta type 1G

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

2.2

DANN

Benign

0.60

DEOGEN2

Benign

0.0056

.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.073

T;T

MetaRNN

Benign

8.7e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.51

.;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

Sift4G

Benign

0.82

T;T

Polyphen

0.0

.;B

Vest4

0.010

MPC

0.22

ClinPred

0.0024

GERP RS

1.1

Varity_R

0.020

gMVP

0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over