17-68537592-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017565.4(FAM20A):​c.1511C>T​(p.Thr504Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 1,613,700 control chromosomes in the GnomAD database, including 13 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00054 ( 9 hom. )

Consequence

FAM20A
NM_017565.4 missense

Scores

15

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.11
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=0.0023069382).
BP6
Variant 17-68537592-G-A is Benign according to our data. Variant chr17-68537592-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 369223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00506 (771/152306) while in subpopulation AFR AF= 0.0172 (713/41562). AF 95% confidence interval is 0.0161. There are 4 homozygotes in gnomad4. There are 377 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FAM20ANM_017565.4 linkuse as main transcriptc.1511C>T p.Thr504Ile 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.1511C>T p.Thr504Ile missense_variant 11/111 NM_017565.4 ENSP00000468308 P1

Frequencies

GnomAD3 genomes
AF:
0.00500
AC:
761
AN:
152188
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0170
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00268
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00156
AC:
391
AN:
250598
Hom.:
8
AF XY:
0.00123
AC XY:
167
AN XY:
135430
show subpopulations
Gnomad AFR exome
AF:
0.0182
Gnomad AMR exome
AF:
0.00191
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000656
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000794
Gnomad OTH exome
AF:
0.00327
GnomAD4 exome
AF:
0.000545
AC:
796
AN:
1461394
Hom.:
9
Cov.:
35
AF XY:
0.000455
AC XY:
331
AN XY:
726922
show subpopulations
Gnomad4 AFR exome
AF:
0.0179
Gnomad4 AMR exome
AF:
0.00206
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.00114
GnomAD4 genome
AF:
0.00506
AC:
771
AN:
152306
Hom.:
4
Cov.:
32
AF XY:
0.00506
AC XY:
377
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0172
Gnomad4 AMR
AF:
0.00268
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.000847
Hom.:
3
Bravo
AF:
0.00584
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.0152
AC:
67
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00191
AC:
232
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000218
EpiControl
AF:
0.000297

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 15, 2024- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:1
Benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoNov 03, 2022- -
Acrodysostosis Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Carney complex Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
10
DANN
Benign
0.76
DEOGEN2
Benign
0.13
.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.94
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.54
T;T
MetaRNN
Benign
0.0023
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.37
.;N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.26
T
Sift4G
Benign
0.97
T;T
Polyphen
0.0
.;B
Vest4
0.019
MVP
0.34
MPC
0.17
ClinPred
0.000033
T
GERP RS
0.80
Varity_R
0.050
gMVP
0.18

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: rs146689929; hg19: chr17-66533733; API