rs200182983

chr22-50626882-G-Achr22-50626882-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000487.6(ARSA):c.636C>T(p.Ala212=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000446 in 1,613,512 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A212A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (9 hom.)
• Consequence: ARSA NM_000487.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.29

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-50626882-G-A is Benign according to our data. Variant chr22-50626882-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626882-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000461 (674/1461142) while in subpopulation SAS AF= 0.00406 (350/86256). AF 95% confidence interval is 0.00371. There are 9 homozygotes in gnomad4_exome. There are 433 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6	c.636C>T	p.Ala212=	synonymous_variant	3/8	ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10	c.636C>T	p.Ala212=	synonymous_variant	3/8	1	NM_000487.6	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000726 AC: 182 AN: 250676 Hom.: 0 AF XY: 0.000973 AC XY: 132 AN XY: 135692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00441

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000336

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000461 AC: 674 AN: 1461142 Hom.: 9 Cov.: 33 AF XY: 0.000596 AC XY: 433 AN XY: 726846

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00406

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74504

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000274 Hom.: 0

Bravo AF: 0.000215

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 26, 2012	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

ARSA: BP4, BP7 -

Metachromatic leukodystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.57
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200182983; hg19: chr22-51065310; COSMIC: COSV53351096; COSMIC: COSV53351096;