17-68537267-C-T

Position:

• chr17-68537267-C-T

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.*210G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 722,954 control chromosomes in the GnomAD database, including 378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (41 hom., cov: 32)
  • Exomes 𝑓: 0.014 (337 hom.)
• Consequence: FAM20A NM_017565.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.44

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 (BayesDel_noAF=-0.88).
• BP6: Variant 17-68537267-C-T is Benign according to our data. Variant chr17-68537267-C-T is described in ClinVar as [Benign]. Clinvar id is 1249313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM20A	NM_017565.4	c.*210G>A		3_prime_UTR_variant	11/11	ENST00000592554.2	NP_060035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM20A	ENST00000592554.2	c.*210G>A		3_prime_UTR_variant	11/11	1	NM_017565.4	ENSP00000468308	P1

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1010 AN: 152108 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0888

Gnomad SAS AF: 0.0864

Gnomad FIN AF: 0.00642

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.0210 AC: 2742 AN: 130712 Hom.: 112 AF XY: 0.0255 AC XY: 1817 AN XY: 71178

Gnomad AFR exome AF: 0.000320

Gnomad AMR exome AF: 0.000659

Gnomad ASJ exome AF: 0.000632

Gnomad EAS exome AF: 0.0824

Gnomad SAS exome AF: 0.0796

Gnomad FIN exome AF: 0.00775

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.00527

GnomAD4 exome AF: 0.0136 AC: 7753 AN: 570728 Hom.: 337 Cov.: 6 AF XY: 0.0173 AC XY: 5292 AN XY: 306432

Gnomad4 AFR exome AF: 0.000188

Gnomad4 AMR exome AF: 0.00109

Gnomad4 ASJ exome AF: 0.000763

Gnomad4 EAS exome AF: 0.0739

Gnomad4 SAS exome AF: 0.0776

Gnomad4 FIN exome AF: 0.00646

Gnomad4 NFE exome AF: 0.000414

Gnomad4 OTH exome AF: 0.00764

GnomAD4 genome AF: 0.00662 AC: 1007 AN: 152226 Hom.: 41 Cov.: 32 AF XY: 0.00885 AC XY: 659 AN XY: 74428

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0881

Gnomad4 SAS AF: 0.0869

Gnomad4 FIN AF: 0.00642

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00158 Hom.: 1

Bravo AF: 0.00466

Asia WGS AF: 0.0820 AC: 287 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2020	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.66
DANN	Benign	0.86

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: rs2286554; hg19: chr17-66533408;