17-68537503-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017565.4(FAM20A):ā€‹c.1600T>Cā€‹(p.Ser534Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

FAM20A
NM_017565.4 missense

Scores

2
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.310
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.068074256).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FAM20ANM_017565.4 linkuse as main transcriptc.1600T>C p.Ser534Pro 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.1600T>C p.Ser534Pro missense_variant 11/111 NM_017565.4 ENSP00000468308 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461746
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727140
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 09, 2023The c.1600T>C (p.S534P) alteration is located in exon 11 (coding exon 11) of the FAM20A gene. This alteration results from a T to C substitution at nucleotide position 1600, causing the serine (S) at amino acid position 534 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.082
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Benign
0.010
.;T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.55
T;T
M_CAP
Benign
0.036
D
MetaRNN
Benign
0.068
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Uncertain
2.3
.;M
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.33
T
Sift4G
Benign
0.13
T;T
Polyphen
0.0030
.;B
Vest4
0.11
MutPred
0.10
.;Loss of glycosylation at S534 (P = 0.032);
MVP
0.24
MPC
0.20
ClinPred
0.079
T
GERP RS
3.6
Varity_R
0.10
gMVP
0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-66533644; API