rs200012526

Variant names:

• chr5-150302287-G-A
• rs200012526
• NM_001012301.4:c.87C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001012301.4(ARSI):​c.87C>T​(p.Ala29Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,604,888 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (22 hom.)
• Consequence: ARSI NM_001012301.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.931
• Publications: 1 publications found

Genes affected

ARSI (HGNC:32521): (arylsulfatase family member I) This gene encodes a protein that belongs to a large family of sulfatases that hydrolyze sulfate esters and sulfamates. Members of this family play a role in several cellular processes, including hormone synthesis, cell signaling in development and degradation of macromolecules. The protein encoded by this gene is thought to be secreted, and to function in extracellular space. [provided by RefSeq, Jul 2016]

ARSI Gene-Disease associations (from GenCC):

• autosomal recessive spastic paraplegia type 66

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-150302287-G-A is Benign according to our data. Variant chr5-150302287-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 465198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.931 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012301.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSI	NM_001012301.4	MANE Select	c.87C>T	p.Ala29Ala	synonymous	Exon 1 of 2	NP_001012301.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSI	ENST00000328668.8	TSL:1 MANE Select	c.87C>T	p.Ala29Ala	synonymous	Exon 1 of 2	ENSP00000333395.7
	ARSI	ENST00000515301.2	TSL:4	c.-118-3675C>T		intron	N/A	ENSP00000426879.2
	ARSI	ENST00000509146.1	TSL:4	c.-118-3675C>T		intron	N/A	ENSP00000420955.1

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 540 AN: 152142 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00471

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00334 AC: 753 AN: 225664 AF XY: 0.00326

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00618

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000455

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00448 AC: 6508 AN: 1452630 Hom.: 22 Cov.: 31 AF XY: 0.00436 AC XY: 3145 AN XY: 722044

African (AFR) AF: 0.00207 AC: 69 AN: 33268

American (AMR) AF: 0.00599 AC: 259 AN: 43246

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25780

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.00 AC: 0 AN: 84946

European-Finnish (FIN) AF: 0.000466 AC: 24 AN: 51522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00537 AC: 5957 AN: 1108722

Other (OTH) AF: 0.00327 AC: 196 AN: 59964

GnomAD4 genome AF: 0.00355 AC: 540 AN: 152258 Hom.: 3 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74428

African (AFR) AF: 0.00219 AC: 91 AN: 41564

American (AMR) AF: 0.00771 AC: 118 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00471 AC: 320 AN: 67994

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00358 Hom.: 0

Bravo AF: 0.00421

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.9
DANN	Benign	0.93
PhyloP100		-0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200012526; hg19: chr5-149681850;