rs77943970

Variant names:

• chr5-150298255-G-A
• rs77943970
• NM_001012301.4:c.669C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001012301.4(ARSI):​c.669C>T​(p.His223His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,613,926 control chromosomes in the GnomAD database, including 1,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.037 (125 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1284 hom.)
• Consequence: ARSI NM_001012301.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.458
• Publications: 6 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=-0.55).
• BP6: Variant 5-150298255-G-A is Benign according to our data. Variant chr5-150298255-G-A is described in ClinVar as Benign. ClinVar VariationId is 465196.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.458 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0373 (5675/152304) while in subpopulation AMR AF = 0.0418 (640/15310). AF 95% confidence interval is 0.0403. There are 125 homozygotes in GnomAd4. There are 2842 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 125 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSI	NM_001012301.4	MANE Select	c.669C>T	p.His223His	synonymous	Exon 2 of 2	NP_001012301.1	Q5FYB1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSI	ENST00000328668.8	TSL:1 MANE Select	c.669C>T	p.His223His	synonymous	Exon 2 of 2	ENSP00000333395.7	Q5FYB1-1
	ARSI	ENST00000515301.2	TSL:4	c.240C>T	p.His80His	synonymous	Exon 2 of 2	ENSP00000426879.2	Q5FYB1-2
	ARSI	ENST00000509146.1	TSL:4	c.240C>T	p.His80His	synonymous	Exon 2 of 2	ENSP00000420955.1	D6RDH0

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5672 AN: 152188 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0419

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.0747

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0444

GnomAD2 exomes AF: 0.0366 AC: 9155 AN: 250462 AF XY: 0.0361

Gnomad AFR exome AF: 0.0235

Gnomad AMR exome AF: 0.0296

Gnomad ASJ exome AF: 0.0688

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0760

Gnomad NFE exome AF: 0.0436

Gnomad OTH exome AF: 0.0434

GnomAD4 exome AF: 0.0396 AC: 57937 AN: 1461622 Hom.: 1284 Cov.: 30 AF XY: 0.0387 AC XY: 28109 AN XY: 727118

African (AFR) AF: 0.0244 AC: 818 AN: 33476

American (AMR) AF: 0.0319 AC: 1426 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0678 AC: 1773 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00852 AC: 735 AN: 86248

European-Finnish (FIN) AF: 0.0739 AC: 3941 AN: 53356

Middle Eastern (MID) AF: 0.0387 AC: 223 AN: 5768

European-Non Finnish (NFE) AF: 0.0420 AC: 46675 AN: 1111842

Other (OTH) AF: 0.0388 AC: 2343 AN: 60380

GnomAD4 genome AF: 0.0373 AC: 5675 AN: 152304 Hom.: 125 Cov.: 32 AF XY: 0.0382 AC XY: 2842 AN XY: 74476

African (AFR) AF: 0.0236 AC: 980 AN: 41568

American (AMR) AF: 0.0418 AC: 640 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4830

European-Finnish (FIN) AF: 0.0747 AC: 793 AN: 10614

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0416 AC: 2831 AN: 68008

Other (OTH) AF: 0.0440 AC: 93 AN: 2116

Alfa AF: 0.0419 Hom.: 79

Bravo AF: 0.0363

Asia WGS AF: 0.00693 AC: 25 AN: 3478

EpiCase AF: 0.0413

EpiControl AF: 0.0464

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.9
DANN	Benign	0.56
PhyloP100		0.46
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs77943970; hg19: chr5-149677818; COSMIC: COSV60817009;