22-50625640-G-A

Variant names:

• chr22-50625640-G-A
• rs6151425
• NM_000487.6:c.1149C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000487.6(ARSA):​c.1149C>T​(p.Asp383Asp) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.31
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• metachromatic leukodystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• metachromatic leukodystrophy, juvenile form

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 93117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 136 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.1149C>T	p.Asp383Asp	synonymous_variant	Exon 7 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.1149C>T	p.Asp383Asp	synonymous_variant	Exon 7 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6166 AN: 152152 Hom.: 135 Cov.: 34

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

GnomAD2 exomes AF: 0.0339 AC: 8506 AN: 251008 AF XY: 0.0346

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 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.: 45 AF XY: 0.0380 AC XY: 27613 AN XY: 726862

African (AFR) AF: 0.0506 AC: 1693 AN: 33464

American (AMR) AF: 0.0177 AC: 793 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0670 AC: 1751 AN: 26120

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39698

South Asian (SAS) AF: 0.0332 AC: 2864 AN: 86246

European-Finnish (FIN) AF: 0.0462 AC: 2451 AN: 53082

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5768

European-Non Finnish (NFE) AF: 0.0393 AC: 43720 AN: 1111612

Other (OTH) AF: 0.0379 AC: 2287 AN: 60360

GnomAD4 genome AF: 0.0405 AC: 6166 AN: 152270 Hom.: 136 Cov.: 34 AF XY: 0.0407 AC XY: 3028 AN XY: 74472

African (AFR) AF: 0.0517 AC: 2148 AN: 41560

American (AMR) AF: 0.0297 AC: 455 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0271 AC: 131 AN: 4826

European-Finnish (FIN) AF: 0.0503 AC: 534 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0385 AC: 2619 AN: 67992

Other (OTH) AF: 0.0365 AC: 77 AN: 2112

Alfa AF: 0.0364 Hom.: 387

Bravo AF: 0.0396

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0385

EpiControl AF: 0.0353

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 24, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Metachromatic leukodystrophy Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.4
DANN	Benign	0.64
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6151425; hg19: chr22-51064068;