17-68542098-G-T

Position:

chr17-68542098-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017565.4(FAM20A):c.996C>A(p.Asn332Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,613,778 control chromosomes in the GnomAD database, including 76,585 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7512 hom., cov: 32)

Exomes 𝑓: 0.30 ( 69073 hom. )

Consequence

FAM20A
NM_017565.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.59

Variant links:

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]

FAM20A links:

FAM20A (HGNC:):

FAM20A links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.4967065E-4).

BP6

Variant 17-68542098-G-T is Benign according to our data. Variant chr17-68542098-G-T is described in ClinVar as [Benign]. Clinvar id is 260833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM20A	NM_017565.4 linkuse as main transcript	c.996C>A	p.Asn332Lys	missense_variant	7/11	ENST00000592554.2	NP_060035.2	Q96MK3L8B8N7Q8IYA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM20A	ENST00000592554.2 linkuse as main transcript	c.996C>A	p.Asn332Lys	missense_variant	7/11	1	NM_017565.4	ENSP00000468308.1		Q96MK3

Frequencies

GnomAD3 genomes

AF:

0.308

AC:

46716

AN:

151896

Hom.:

7501

Cov.:

show subpopulations

Gnomad AFR

AF:

0.268

Gnomad AMI

AF:

0.361

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.554

Gnomad SAS

AF:

0.271

Gnomad FIN

AF:

0.320

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.337

GnomAD3 exomes

AF:

0.332

AC:

83294

AN:

251242

Hom.:

14839

AF XY:

0.325

AC XY:

44193

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.258

Gnomad AMR exome

AF:

0.443

Gnomad ASJ exome

AF:

0.262

Gnomad EAS exome

AF:

0.577

Gnomad SAS exome

AF:

0.277

Gnomad FIN exome

AF:

0.322

Gnomad NFE exome

AF:

0.291

Gnomad OTH exome

AF:

0.328

GnomAD4 exome

AF:

0.304

AC:

443759

AN:

1461766

Hom.:

69073

Cov.:

AF XY:

0.302

AC XY:

219440

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.267

Gnomad4 AMR exome

AF:

0.431

Gnomad4 ASJ exome

AF:

0.265

Gnomad4 EAS exome

AF:

0.534

Gnomad4 SAS exome

AF:

0.284

Gnomad4 FIN exome

AF:

0.324

Gnomad4 NFE exome

AF:

0.292

Gnomad4 OTH exome

AF:

0.310

GnomAD4 genome

AF:

0.308

AC:

46763

AN:

152012

Hom.:

7512

Cov.:

AF XY:

0.311

AC XY:

23136

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.268

Gnomad4 AMR

AF:

0.404

Gnomad4 ASJ

AF:

0.255

Gnomad4 EAS

AF:

0.556

Gnomad4 SAS

AF:

0.270

Gnomad4 FIN

AF:

0.320

Gnomad4 NFE

AF:

0.293

Gnomad4 OTH

AF:

0.339

Alfa

AF:

0.297

Hom.:

17453

Bravo

AF:

0.313

TwinsUK

AF:

0.289

AC:

1072

ALSPAC

AF:

0.302

AC:

1162

ESP6500AA

AF:

0.274

AC:

1208

ESP6500EA

AF:

0.303

AC:

2606

ExAC

AF:

0.324

AC:

39275

Asia WGS

AF:

0.385

AC:

1340

AN:

3478

EpiCase

AF:

0.292

EpiControl

AF:

0.297

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

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

0.16

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.70

MetaRNN

Benign

0.00035

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.48

Sift4G

Benign

1.0

Polyphen

0.81

Vest4

0.089

MutPred

0.29

Gain of ubiquitination at N332 (P = 0.0211);

MPC

0.53

ClinPred

0.0083

GERP RS

5.0

Varity_R

0.21

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over