17-68537514-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.73 (40888 hom., cov: 30)
  • Exomes 𝑓: 0.68 (338718 hom.)
• Consequence: FAM20A NM_017565.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.172

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]

ACMG classification

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	UniProt
FAM20A	NM_017565.4	c.1589T>C	p.Leu530Ser	missense_variant	11/11	ENST00000592554.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.728 AC: 110611 AN: 151854 Hom.: 40853 Cov.: 30

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

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

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

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -

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	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	2.2
Dann	Benign	0.60
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
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

Other links and lift over

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