chr17-68420363-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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:

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:

ENSG00000267009 (HGNC:):

ENSG00000267009 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=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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

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

GnomAD3 exomes

AF:

0.00255

AC:

640

AN:

251436

Hom.:

AF XY:

0.00271

AC XY:

368

AN XY:

135884

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 SAS exome

AF:

0.000719

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

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00432

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000927

Gnomad4 FIN exome

AF:

0.00165

Gnomad4 NFE exome

AF:

0.00358

Gnomad4 OTH exome

AF:

0.00238

GnomAD4 genome

AF:

0.00235

AC:

357

AN:

152230

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

158

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00289

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00387

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00330

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

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;.

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

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