chr17-68538004-A-C

Variant names:

• chr17-68538004-A-C
• rs16973034
• NM_017565.4:c.1362-263T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_017565.4(FAM20A):​c.1362-263T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 152,264 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0040 (3 hom., cov: 33)
• Consequence: FAM20A NM_017565.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.648
• Publications: 2 publications found

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]

PRKAR1A Gene-Disease associations (from GenCC):

• Acrodysostosis 1 with or without hormone resistance

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• acrodysostosis with multiple hormone resistance

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• Carney complex, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pigmented nodular adrenocortical disease, primary, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• acrodysostosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Carney complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial myxoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary pigmented nodular adrenocortical disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00404 (615/152264) while in subpopulation NFE AF = 0.00723 (492/68018). AF 95% confidence interval is 0.00671. There are 3 homozygotes in GnomAd4. There are 274 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017565.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20A	NM_017565.4	MANE Select	c.1362-263T>G		intron	N/A	NP_060035.2
	FAM20A	NM_001243746.2		c.948-263T>G		intron	N/A	NP_001230675.1
	PRKAR1A	NM_001276290.1		c.973+8003A>C		intron	N/A	NP_001263219.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20A	ENST00000592554.2	TSL:1 MANE Select	c.1362-263T>G		intron	N/A	ENSP00000468308.1
	FAM20A	ENST00000226094.9	TSL:1	n.1040-263T>G		intron	N/A
	PRKAR1A	ENST00000585981.6	TSL:5	c.973+8003A>C		intron	N/A	ENSP00000467311.2

Frequencies

GnomAD3 genomes AF: 0.00404 AC: 615 AN: 152146 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00575

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00404 AC: 615 AN: 152264 Hom.: 3 Cov.: 33 AF XY: 0.00368 AC XY: 274 AN XY: 74446

African (AFR) AF: 0.00128 AC: 53 AN: 41556

American (AMR) AF: 0.00281 AC: 43 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00723 AC: 492 AN: 68018

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.000622 Hom.: 59

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.074
DANN	Benign	0.53
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16973034; hg19: chr17-66534145;