22-50622771-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000487.6(ARSA):c.*2374C>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 0.0272 in 152,318 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (78 hom., cov: 32)
  • Exomes 𝑓: 0.053 (0 hom.)
• Consequence: ARSA NM_000487.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.236

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=-0.76).
• BP6: Variant 22-50622771-G-T is Benign according to our data. Variant chr22-50622771-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 342183.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0272 (4139/152280) while in subpopulation NFE AF= 0.0386 (2623/68022). AF 95% confidence interval is 0.0373. There are 78 homozygotes in gnomad4. There are 2061 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 78 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6	c.*2374C>A		3_prime_UTR_variant	8/8	ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10	c.*2374C>A		3_prime_UTR_variant	8/8	1	NM_000487.6	P1
ARSA	ENST00000610191.1	n.556C>A		non_coding_transcript_exon_variant	1/1
ARSA	ENST00000608497.1	c.*350C>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4141 AN: 152162 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.0567

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0504

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0386

Gnomad OTH AF: 0.0254

GnomAD4 exome AF: 0.0526 AC: 2 AN: 38 Hom.: 0 Cov.: 0 AF XY: 0.0833 AC XY: 2 AN XY: 24

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.0385

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0272 AC: 4139 AN: 152280 Hom.: 78 Cov.: 32 AF XY: 0.0277 AC XY: 2061 AN XY: 74448

Gnomad4 AFR AF: 0.00657

Gnomad4 AMR AF: 0.0210

Gnomad4 ASJ AF: 0.0567

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0272

Gnomad4 FIN AF: 0.0504

Gnomad4 NFE AF: 0.0386

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0316 Hom.: 12

Bravo AF: 0.0240

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metachromatic leukodystrophy Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	3.8
Dann	Benign	0.86

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11704557; hg19: chr22-51061199;