NM_017565.4:c.*210G>A

Variant names:

• chr17-68537267-C-T
• rs2286554
• NM_017565.4:c.*210G>A

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.*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
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20A	NM_017565.4	MANE Select	c.*210G>A		3_prime_UTR	Exon 11 of 11	NP_060035.2	Q96MK3
	FAM20A	NM_001243746.2		c.*210G>A		3_prime_UTR	Exon 12 of 12	NP_001230675.1
	PRKAR1A	NM_001276290.1		c.973+7266C>T		intron	N/A	NP_001263219.1	P10644-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM20A	ENST00000592554.2	TSL:1 MANE Select	c.*210G>A		3_prime_UTR	Exon 11 of 11	ENSP00000468308.1	Q96MK3
	FAM20A	ENST00000226094.9	TSL:1	n.1514G>A		non_coding_transcript_exon	Exon 11 of 11
	FAM20A	ENST00000882126.1		c.*210G>A		3_prime_UTR	Exon 12 of 12	ENSP00000552185.1

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

GnomAD2 exomes AF: 0.0210 AC: 2742 AN: 130712 AF XY: 0.0255

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 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

African (AFR) AF: 0.000188 AC: 3 AN: 15992

American (AMR) AF: 0.00109 AC: 37 AN: 34064

Ashkenazi Jewish (ASJ) AF: 0.000763 AC: 15 AN: 19656

East Asian (EAS) AF: 0.0739 AC: 2269 AN: 30698

South Asian (SAS) AF: 0.0776 AC: 4844 AN: 62386

European-Finnish (FIN) AF: 0.00646 AC: 204 AN: 31592

Middle Eastern (MID) AF: 0.00205 AC: 5 AN: 2444

European-Non Finnish (NFE) AF: 0.000414 AC: 142 AN: 343284

Other (OTH) AF: 0.00764 AC: 234 AN: 30612

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

African (AFR) AF: 0.000217 AC: 9 AN: 41538

American (AMR) AF: 0.00157 AC: 24 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0881 AC: 456 AN: 5178

South Asian (SAS) AF: 0.0869 AC: 419 AN: 4820

European-Finnish (FIN) AF: 0.00642 AC: 68 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68008

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00126 Hom.: 1

Bravo AF: 0.00466

Asia WGS AF: 0.0820 AC: 287 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.66
DANN	Benign	0.86
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2286554; hg19: chr17-66533408;