chr5-150297810-C-G

Position:

• chr5-150297810-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSI	NM_001012301.4	c.1114G>C	p.Asp372His	missense_variant	2/2	ENST00000328668.8	NP_001012301.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSI	ENST00000328668.8	c.1114G>C	p.Asp372His	missense_variant	2/2	1	NM_001012301.4	ENSP00000333395.7
ARSI	ENST00000515301.2	c.685G>C	p.Asp229His	missense_variant	2/2	4		ENSP00000426879.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 20, 2019

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ARSI-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 372 of the ARSI protein (p.Asp372His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.034	D;D
Sift4G	Uncertain	0.032	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs150211860; hg19: chr5-149677373;