Genetic Variant NM_001012301.4:c.312-121T>C (chr5-150298733-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001012301.4(ARSI):c.312-121T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 851,110 control chromosomes in the GnomAD database, including 238,817 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.68 ( 36384 hom., cov: 32)

Exomes 𝑓: 0.76 ( 202433 hom. )

Consequence

ARSI
NM_001012301.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.813

Publications

2 publications found

Variant links:

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

ARSI links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

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.312-121T>C		intron	N/A	NP_001012301.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ARSI	ENST00000328668.8	TSL:1 MANE Select	c.312-121T>C	intron	N/A	ENSP00000333395.7
ARSI	ENST00000515301.2	TSL:4	c.-118-121T>C	intron	N/A	ENSP00000426879.2
ARSI	ENST00000509146.1	TSL:4	c.-118-121T>C	intron	N/A	ENSP00000420955.1

Frequencies

GnomAD3 genomes

AF:

0.685

AC:

104031

AN:

151976

Hom.:

36379

Cov.:

show subpopulations

Gnomad AFR

AF:

0.527

Gnomad AMI

AF:

0.745

Gnomad AMR

AF:

0.650

Gnomad ASJ

AF:

0.754

Gnomad EAS

AF:

0.688

Gnomad SAS

AF:

0.746

Gnomad FIN

AF:

0.748

Gnomad MID

AF:

0.674

Gnomad NFE

AF:

0.770

Gnomad OTH

AF:

0.672

GnomAD4 exome

AF:

0.758

AC:

530018

AN:

699014

Hom.:

202433

AF XY:

0.759

AC XY:

269182

AN XY:

354884

show subpopulations

African (AFR)

AF:

0.531

AC:

8933

AN:

16820

American (AMR)

AF:

0.617

AC:

11950

AN:

19356

Ashkenazi Jewish (ASJ)

AF:

0.748

AC:

11371

AN:

15192

East Asian (EAS)

AF:

0.742

AC:

23963

AN:

32294

South Asian (SAS)

AF:

0.745

AC:

37824

AN:

50780

European-Finnish (FIN)

AF:

0.764

AC:

33496

AN:

43856

Middle Eastern (MID)

AF:

0.655

AC:

1591

AN:

2428

European-Non Finnish (NFE)

AF:

0.777

AC:

376127

AN:

484352

Other (OTH)

AF:

0.730

AC:

24763

AN:

33936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

7110

14219

21329

28438

35548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6208

12416

18624

24832

31040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.684

AC:

104063

AN:

152096

Hom.:

36384

Cov.:

AF XY:

0.683

AC XY:

50797

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.526

AC:

21827

AN:

41474

American (AMR)

AF:

0.649

AC:

9919

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.754

AC:

2617

AN:

3472

East Asian (EAS)

AF:

0.688

AC:

3556

AN:

5172

South Asian (SAS)

AF:

0.747

AC:

3597

AN:

4816

European-Finnish (FIN)

AF:

0.748

AC:

7914

AN:

10586

Middle Eastern (MID)

AF:

0.667

AC:

196

AN:

294

European-Non Finnish (NFE)

AF:

0.770

AC:

52337

AN:

67982

Other (OTH)

AF:

0.673

AC:

1421

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1628

3256

4885

6513

8141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

818

1636

2454

3272

4090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.708

Hom.:

5666

Bravo

AF:

0.667

Asia WGS

AF:

0.703

AC:

2443

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

1.1

(source)

DANN

Benign

0.49

PhyloP100

-0.81

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over