17-68537514-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):ā€‹c.1589T>Cā€‹(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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.73 ( 40888 hom., cov: 30)
Exomes š‘“: 0.68 ( 338718 hom. )

Consequence

FAM20A
NM_017565.4 missense

Scores

15

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]
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]

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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
FAM20ANM_017565.4 linkuse as main transcriptc.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
FAM20AENST00000592554.2 linkuse as main transcriptc.1589T>C p.Leu530Ser missense_variant 11/111 NM_017565.4 ENSP00000468308 P1

Frequencies

GnomAD3 genomes
AF:
0.728
AC:
110611
AN:
151854
Hom.:
40853
Cov.:
30
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.:
67
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.:
30
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 submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 20, 2019- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Amelogenesis imperfecta type 1G Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.051
BayesDel_addAF
Benign
-0.65
T
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
N
LIST_S2
Benign
0.073
T;T
MetaRNN
Benign
8.7e-7
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.51
.;N
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.29
T
Sift4G
Benign
0.82
T;T
Polyphen
0.0
.;B
Vest4
0.010
MPC
0.22
ClinPred
0.0024
T
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.

Other links and lift over

dbSNP: rs2907373; hg19: chr17-66533655; COSMIC: COSV56836832; COSMIC: COSV56836832; API