chr22-50623623-G-T

Position:

• chr22-50623623-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000487.6(ARSA):​c.*1522C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 151,934 control chromosomes in the GnomAD database, including 5,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.27 (5643 hom., cov: 31)
• Consequence: ARSA NM_000487.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.336

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 22-50623623-G-T is Benign according to our data. Variant chr22-50623623-G-T is described in ClinVar as [Benign]. Clinvar id is 342198.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6	c.*1522C>A		3_prime_UTR_variant	8/8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.*1522C>A		3_prime_UTR_variant	8/8	1	NM_000487.6	ENSP00000216124	P1
ARSA	ENST00000608497.1	c.*93+151C>A		intron_variant, NMD_transcript_variant		3		ENSP00000477013

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40379 AN: 151816 Hom.: 5624 Cov.: 31

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.316

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.252

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.266 AC: 40449 AN: 151934 Hom.: 5643 Cov.: 31 AF XY: 0.267 AC XY: 19855 AN XY: 74252

Gnomad4 AFR AF: 0.320

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.401

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.257

Alfa AF: 0.122 Hom.: 206

Bravo AF: 0.278

Asia WGS AF: 0.367 AC: 1276 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metachromatic leukodystrophy Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.1
DANN	Benign	0.44

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6009939; hg19: chr22-51062051;