rs6151425

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000487.6(ARSA):c.1149C>T(p.Asp383=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0384 in 1,613,342 control chromosomes in the GnomAD database, including 1,354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 136 hom., cov: 34)

Exomes 𝑓: 0.038 ( 1218 hom. )

Consequence

ARSA
NM_000487.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.31

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 22-50625640-G-A is Benign according to our data. Variant chr22-50625640-G-A is described in ClinVar as [Benign]. Clinvar id is 93117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50625640-G-A is described in Lovd as [Benign]. Variant chr22-50625640-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.31 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0405 (6166/152270) while in subpopulation AFR AF= 0.0517 (2148/41560). AF 95% confidence interval is 0.0499. There are 136 homozygotes in gnomad4. There are 3028 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 136 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6 linkuse as main transcript	c.1149C>T	p.Asp383=	synonymous_variant	7/8	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.1149C>T	p.Asp383=	synonymous_variant	7/8	1	NM_000487.6	ENSP00000216124	P1

Frequencies

GnomAD3 genomes

AF:

0.0405

AC:

6166

AN:

152152

Hom.:

135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0518

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.0298

Gnomad ASJ

AF:

0.0550

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0273

Gnomad FIN

AF:

0.0503

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0385

Gnomad OTH

AF:

0.0373

GnomAD3 exomes

AF:

0.0339

AC:

8506

AN:

251008

Hom.:

181

AF XY:

0.0346

AC XY:

4702

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.0480

Gnomad AMR exome

AF:

0.0162

Gnomad ASJ exome

AF:

0.0674

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0324

Gnomad FIN exome

AF:

0.0495

Gnomad NFE exome

AF:

0.0373

Gnomad OTH exome

AF:

0.0317

GnomAD4 exome

AF:

0.0381

AC:

55736

AN:

1461072

Hom.:

1218

Cov.:

AF XY:

0.0380

AC XY:

27613

AN XY:

726862

show subpopulations

Gnomad4 AFR exome

AF:

0.0506

Gnomad4 AMR exome

AF:

0.0177

Gnomad4 ASJ exome

AF:

0.0670

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0332

Gnomad4 FIN exome

AF:

0.0462

Gnomad4 NFE exome

AF:

0.0393

Gnomad4 OTH exome

AF:

0.0379

GnomAD4 genome

AF:

0.0405

AC:

6166

AN:

152270

Hom.:

136

Cov.:

AF XY:

0.0407

AC XY:

3028

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0517

Gnomad4 AMR

AF:

0.0297

Gnomad4 ASJ

AF:

0.0550

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0271

Gnomad4 FIN

AF:

0.0503

Gnomad4 NFE

AF:

0.0385

Gnomad4 OTH

AF:

0.0365

Alfa

AF:

0.0356

Hom.:

174

Bravo

AF:

0.0396

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0385

EpiControl

AF:

0.0353

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 18, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Metachromatic leukodystrophy

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.4

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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