rs112896077

Variant names:

• chr5-150298240-G-A
• rs112896077
• NM_001012301.4:c.684C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001012301.4(ARSI):​c.684C>T​(p.Pro228Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,614,170 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (13 hom.)
• Consequence: ARSI NM_001012301.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.184
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 5-150298240-G-A is Benign according to our data. Variant chr5-150298240-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 533757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.184 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSI	NM_001012301.4	c.684C>T	p.Pro228Pro	synonymous_variant	Exon 2 of 2	ENST00000328668.8	NP_001012301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSI	ENST00000328668.8	c.684C>T	p.Pro228Pro	synonymous_variant	Exon 2 of 2	1	NM_001012301.4	ENSP00000333395.7
ARSI	ENST00000515301.2	c.255C>T	p.Pro85Pro	synonymous_variant	Exon 2 of 2	4		ENSP00000426879.2
ARSI	ENST00000509146.1	c.255C>T	p.Pro85Pro	synonymous_variant	Exon 2 of 2	4		ENSP00000420955.1

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 426 AN: 152218 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00303 AC: 759 AN: 250866 AF XY: 0.00315

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00470

Gnomad NFE exome AF: 0.00471

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00318 AC: 4647 AN: 1461834 Hom.: 13 Cov.: 30 AF XY: 0.00325 AC XY: 2366 AN XY: 727220

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00154 AC: 69 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 95 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86258

European-Finnish (FIN) AF: 0.00467 AC: 249 AN: 53370

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00358 AC: 3985 AN: 1112004

Other (OTH) AF: 0.00305 AC: 184 AN: 60396

GnomAD4 genome AF: 0.00280 AC: 426 AN: 152336 Hom.: 2 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74494

African (AFR) AF: 0.000601 AC: 25 AN: 41582

American (AMR) AF: 0.00229 AC: 35 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 68028

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00386 Hom.: 2

Bravo AF: 0.00250

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00587

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ARSI: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.6
DANN	Benign	0.79
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs112896077; hg19: chr5-149677803; COSMIC: COSV60816957;