chr22-50623399-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.436
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
ARSANM_000487.6 linkuse as main transcriptc.*1746G>A 3_prime_UTR_variant 8/8 ENST00000216124.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ARSAENST00000216124.10 linkuse as main transcriptc.*1746G>A 3_prime_UTR_variant 8/81 NM_000487.6 P1
ARSAENST00000608497.1 linkuse as main transcriptc.*94-372G>A intron_variant, NMD_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0432
AC:
6573
AN:
152064
Hom.:
123
Cov.:
32
show subpopulations
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
show subpopulations
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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Metachromatic leukodystrophy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs73172277; hg19: chr22-51061827; API