NM_001267727.2:c.1478T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001267727.2(ARSG):c.1478T>C(p.Ile493Thr) variant causes a missense change. The variant allele was found at a frequency of 0.003 in 1,614,120 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 10 hom. )

Consequence

ARSG
NM_001267727.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.19

Publications

9 publications found

Variant links:

Genes affected

ARSG (HGNC:24102): (arylsulfatase G) The protein encoded by this gene belongs to the sulfatase enzyme family. Sulfatases hydrolyze sulfate esters from sulfated steroids, carbohydrates, proteoglycans, and glycolipids. They are involved in hormone biosynthesis, modulation of cell signaling, and degradation of macromolecules. This protein displays arylsulfatase activity at acidic pH, as is typical of lysosomal sulfatases, and has been shown to localize in the lysosomes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]

ARSG links:

ENSG00000267009 (HGNC:):

ENSG00000267009 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 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

PRKAR1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.011539072).

BP6

Variant 17-68420363-T-C is Benign according to our data. Variant chr17-68420363-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 731552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00235 (357/152230) while in subpopulation NFE AF = 0.00387 (263/68012). AF 95% confidence interval is 0.00348. There are 1 homozygotes in GnomAd4. There are 158 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSG	NM_001267727.2 link	c.1478T>C	p.Ile493Thr	missense_variant	Exon 12 of 12	ENST00000621439.5	NP_001254656.1	Q96EG1A0A024R8K1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSG	ENST00000621439.5 link	c.1478T>C	p.Ile493Thr	missense_variant	Exon 12 of 12	5	NM_001267727.2	ENSP00000480910.1		Q96EG1

Frequencies

GnomAD3 genomes

AF:

0.00235

AC:

357

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00289

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00387

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00255

AC:

640

AN:

251436

AF XY:

0.00271

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00413

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00307

AC:

4488

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

2184

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.00114

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

113

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00358

AC:

3984

AN:

1112008

Other (OTH)

AF:

0.00238

AC:

144

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

292

585

877

1170

1462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

288

432

576

720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00235

AC:

357

AN:

152230

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

158

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41552

American (AMR)

AF:

0.00222

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00289

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00387

AC:

263

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00317

Hom.:

Bravo

AF:

0.00230

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00285

AC:

346

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00327

EpiControl

AF:

0.00385

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ARSG: BP4 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ARSG-related disorder

Benign:1

Sep 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

T;T;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

.;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Pathogenic

3.0

M;M;.

PhyloP100

7.2

PrimateAI

Benign

0.41

REVEL

Uncertain

0.41

Sift4G

Uncertain

0.045

D;D;D

Polyphen

0.91

P;P;.

Vest4

0.39

MVP

0.76

MPC

0.99

ClinPred

0.049

GERP RS

5.9

Varity_R

0.087

gMVP

0.85

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over