17-68542277-G-A

Variant names:

• chr17-68542277-G-A
• rs2302235
• NM_017565.4:c.929-112C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017565.4(FAM20A):​c.929-112C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,154,794 control chromosomes in the GnomAD database, including 11,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1396 hom., cov: 32)
  • Exomes 𝑓: 0.14 (10061 hom.)
• Consequence: FAM20A NM_017565.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.493

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-68542277-G-A is Benign according to our data. Variant chr17-68542277-G-A is described in ClinVar as [Benign]. Clinvar id is 1237093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM20A	NM_017565.4	c.929-112C>T		intron_variant	Intron 6 of 10	ENST00000592554.2	NP_060035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM20A	ENST00000592554.2	c.929-112C>T		intron_variant	Intron 6 of 10	1	NM_017565.4	ENSP00000468308.1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20316 AN: 152022 Hom.: 1396 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.132

GnomAD4 exome AF: 0.138 AC: 138355 AN: 1002654 Hom.: 10061 AF XY: 0.140 AC XY: 71572 AN XY: 509906

Gnomad4 AFR exome AF: 0.123 AC: 2928 AN: 23844

Gnomad4 AMR exome AF: 0.170 AC: 5826 AN: 34346

Gnomad4 ASJ exome AF: 0.117 AC: 2547 AN: 21708

Gnomad4 EAS exome AF: 0.166 AC: 5707 AN: 34406

Gnomad4 SAS exome AF: 0.191 AC: 13447 AN: 70354

Gnomad4 FIN exome AF: 0.107 AC: 4701 AN: 43884

Gnomad4 NFE exome AF: 0.133 AC: 96552 AN: 724404

Gnomad4 Remaining exome AF: 0.137 AC: 6151 AN: 44808

GnomAD4 genome AF: 0.134 AC: 20320 AN: 152140 Hom.: 1396 Cov.: 32 AF XY: 0.134 AC XY: 9950 AN XY: 74386

Gnomad4 AFR AF: 0.123 AC: 0.122999 AN: 0.122999

Gnomad4 AMR AF: 0.154 AC: 0.154103 AN: 0.154103

Gnomad4 ASJ AF: 0.120 AC: 0.120104 AN: 0.120104

Gnomad4 EAS AF: 0.170 AC: 0.169822 AN: 0.169822

Gnomad4 SAS AF: 0.198 AC: 0.198172 AN: 0.198172

Gnomad4 FIN AF: 0.105 AC: 0.105114 AN: 0.105114

Gnomad4 NFE AF: 0.133 AC: 0.133266 AN: 0.133266

Gnomad4 OTH AF: 0.130 AC: 0.130435 AN: 0.130435

Alfa AF: 0.137 Hom.: 304

Bravo AF: 0.139

Asia WGS AF: 0.187 AC: 649 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.4
DANN	Benign	0.60
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2302235; hg19: chr17-66538418; COSMIC: COSV56836065; COSMIC: COSV56836065;