chr22-50623399-C-T

Position:

• chr22-50623399-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000487.6(ARSA):​c.*1746G>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 0.0432 in 152,182 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (123 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARSA NM_000487.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.436

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 22-50623399-C-T is Benign according to our data. Variant chr22-50623399-C-T is described in ClinVar as [Benign]. Clinvar id is 342192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50623399-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0432 (6573/152182) while in subpopulation NFE AF= 0.047 (3198/68002). AF 95% confidence interval is 0.0457. There are 123 homozygotes in gnomad4. There are 3197 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 123 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6	c.*1746G>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.*1746G>A		3_prime_UTR_variant	8/8	1	NM_000487.6	P1
ARSA	ENST00000608497.1	c.*94-372G>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6573 AN: 152064 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0435

Gnomad EAS AF: 0.00944

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0744

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0470

Gnomad OTH AF: 0.0407

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 22 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 14

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0432 AC: 6573 AN: 152182 Hom.: 123 Cov.: 32 AF XY: 0.0430 AC XY: 3197 AN XY: 74422

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.0435

Gnomad4 EAS AF: 0.00927

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.0744

Gnomad4 NFE AF: 0.0470

Gnomad4 OTH AF: 0.0398

Alfa AF: 0.0379 Hom.: 58

Bravo AF: 0.0390

Asia WGS AF: 0.0190 AC: 67 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	-0.93
CADD	Benign	0.78
DANN	Benign	0.46

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs73172277; hg19: chr22-51061827;