5-150297810-C-G

Variant names:

• chr5-150297810-C-G
• rs150211860
• NM_001012301.4:c.1114G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001012301.4(ARSI):​c.1114G>C​(p.Asp372His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D372N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARSI NM_001012301.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.355
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

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.1114G>C	p.Asp372His	missense	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.1114G>C	p.Asp372His	missense	Exon 2 of 2	ENSP00000333395.7	Q5FYB1-1
	ARSI	ENST00000515301.2	TSL:4	c.685G>C	p.Asp229His	missense	Exon 2 of 2	ENSP00000426879.2	Q5FYB1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454060 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 722570

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25586

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52202

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107982

Other (OTH) AF: 0.00 AC: 0 AN: 60046

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		0.35
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.73
Sift	Benign	0.034	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.84		Gain of disorder (P = 0.19)
MVP		0.84
MPC		1.0
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.19
gMVP		0.85
Mutation Taster		=74/26	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: rs150211860; hg19: chr5-149677373;