rs77196282

Variant names:

• chr5-150302283-C-A
• rs77196282
• NM_001012301.4:c.91G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-150302283-C-A
• chr5-150302283-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001012301.4(ARSI):​c.91G>T​(p.Gly31Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,605,262 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (37 hom.)
• Consequence: ARSI NM_001012301.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.42
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023495257).
• BP6: Variant 5-150302283-C-A is Benign according to our data. Variant chr5-150302283-C-A is described in ClinVar as Benign. ClinVar VariationId is 465200.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1995/152230) while in subpopulation AFR AF = 0.0456 (1895/41558). AF 95% confidence interval is 0.0439. There are 50 homozygotes in GnomAd4. There are 936 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 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.91G>T	p.Gly31Trp	missense	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.91G>T	p.Gly31Trp	missense	Exon 1 of 2	ENSP00000333395.7
	ARSI	ENST00000515301.2	TSL:4	c.-118-3671G>T		intron	N/A	ENSP00000426879.2
	ARSI	ENST00000509146.1	TSL:4	c.-118-3671G>T		intron	N/A	ENSP00000420955.1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1990 AN: 152114 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00318 AC: 717 AN: 225804 AF XY: 0.00237

Gnomad AFR exome AF: 0.0469

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000902

GnomAD4 exome AF: 0.00133 AC: 1936 AN: 1453032 Hom.: 37 Cov.: 31 AF XY: 0.00109 AC XY: 787 AN XY: 722254

African (AFR) AF: 0.0464 AC: 1545 AN: 33280

American (AMR) AF: 0.00233 AC: 101 AN: 43336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.0000706 AC: 6 AN: 84992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51530

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5730

European-Non Finnish (NFE) AF: 0.0000821 AC: 91 AN: 1108908

Other (OTH) AF: 0.00303 AC: 182 AN: 59992

GnomAD4 genome AF: 0.0131 AC: 1995 AN: 152230 Hom.: 50 Cov.: 32 AF XY: 0.0126 AC XY: 936 AN XY: 74418

African (AFR) AF: 0.0456 AC: 1895 AN: 41558

American (AMR) AF: 0.00431 AC: 66 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67988

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00231 Hom.: 5

Bravo AF: 0.0151

ESP6500AA AF: 0.0342 AC: 150

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00347 AC: 417

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0023	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.18	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.94	P
Vest4		0.17
MVP		0.61
MPC		0.60
ClinPred		0.013	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.36
Mutation Taster		=97/3	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: rs77196282; hg19: chr5-149681846; COSMIC: COSV106464508;