chr22-50626933-C-A

Position:

chr22-50626933-C-A

Variant summary

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

The NM_000487.6(ARSA):c.585G>T(p.Trp195Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 1,613,172 control chromosomes in the GnomAD database, including 4,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 275 hom., cov: 33)

Exomes 𝑓: 0.070 ( 4138 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 1.05

Variant links:

Genes affected

ARSA (HGNC:713): (arylsulfatase A) The protein encoded by this gene hydrolyzes cerebroside sulfate to cerebroside and sulfate. Defects in this gene lead to metachromatic leucodystrophy (MLD), a progressive demyelination disease which results in a variety of neurological symptoms and ultimately death. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2010]

ARSA 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=0.004769802).

BP6

Variant 22-50626933-C-A is Benign according to our data. Variant chr22-50626933-C-A is described in ClinVar as [Benign]. Clinvar id is 93125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626933-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6 linkuse as main transcript	c.585G>T	p.Trp195Cys	missense_variant	3/8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10 linkuse as main transcript	c.585G>T	p.Trp195Cys	missense_variant	3/8	1	NM_000487.6	ENSP00000216124	P1

Frequencies

GnomAD3 genomes

AF:

0.0511

AC:

7779

AN:

152216

Hom.:

276

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0150

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0340

Gnomad ASJ

AF:

0.0810

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.0780

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0772

Gnomad OTH

AF:

0.0507

GnomAD3 exomes

AF:

0.0529

AC:

13189

AN:

249174

Hom.:

491

AF XY:

0.0535

AC XY:

7243

AN XY:

135288

show subpopulations

Gnomad AFR exome

AF:

0.0127

Gnomad AMR exome

AF:

0.0277

Gnomad ASJ exome

AF:

0.0750

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.0222

Gnomad FIN exome

AF:

0.0752

Gnomad NFE exome

AF:

0.0768

Gnomad OTH exome

AF:

0.0586

GnomAD4 exome

AF:

0.0703

AC:

102707

AN:

1460838

Hom.:

4138

Cov.:

AF XY:

0.0691

AC XY:

50188

AN XY:

726720

show subpopulations

Gnomad4 AFR exome

AF:

0.0110

Gnomad4 AMR exome

AF:

0.0281

Gnomad4 ASJ exome

AF:

0.0691

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0224

Gnomad4 FIN exome

AF:

0.0718

Gnomad4 NFE exome

AF:

0.0806

Gnomad4 OTH exome

AF:

0.0601

GnomAD4 genome

AF:

0.0511

AC:

7778

AN:

152334

Hom.:

275

Cov.:

AF XY:

0.0502

AC XY:

3738

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0150

Gnomad4 AMR

AF:

0.0339

Gnomad4 ASJ

AF:

0.0810

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0153

Gnomad4 FIN

AF:

0.0780

Gnomad4 NFE

AF:

0.0772

Gnomad4 OTH

AF:

0.0502

Alfa

AF:

0.0709

Hom.:

701

Bravo

AF:

0.0458

TwinsUK

AF:

0.0747

AC:

277

ALSPAC

AF:

0.0825

AC:

318

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.0771

AC:

663

ExAC

AF:

0.0527

AC:

6402

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0796

EpiControl

AF:

0.0787

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Metachromatic leukodystrophy

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31836585, 28670130, 8897113) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 25, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Citrullinemia

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T;T;.;T

Eigen

Benign

0.0048

Eigen_PC

Benign

0.041

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.86

.;.;.;D;D

MetaRNN

Benign

0.0048

T;T;T;T;T

MetaSVM

Benign

-0.32

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.73

N;N;N;N;N

REVEL

Uncertain

0.42

Sift

Benign

0.036

D;D;D;D;D

Sift4G

Uncertain

0.032

D;D;D;T;D

Vest4

0.49

ClinPred

0.010

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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