Genetic Variant NM_000046.5:c.1191G>A (chr5-78839378-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000046.5(ARSB):c.1191G>A(p.Pro397Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 1,612,794 control chromosomes in the GnomAD database, including 35,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 7001 hom., cov: 32)

Exomes 𝑓: 0.18 ( 28451 hom. )

Consequence

ARSB
NM_000046.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.29

Publications

33 publications found

Variant links:

Genes affected

ARSB (HGNC:714): (arylsulfatase B) Arylsulfatase B encoded by this gene belongs to the sulfatase family. The arylsulfatase B homodimer hydrolyzes sulfate groups of N-Acetyl-D-galactosamine, chondriotin sulfate, and dermatan sulfate. The protein is targeted to the lysozyme. Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Dec 2016]

ARSB Gene-Disease associations (from GenCC):

mucopolysaccharidosis type 6
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Illumina, G2P

ARSB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 5-78839378-C-T is Benign according to our data. Variant chr5-78839378-C-T is described in ClinVar as Benign. ClinVar VariationId is 92354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.29 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000046.5. 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
	ARSB	NM_000046.5	MANE Select	c.1191G>A	p.Pro397Pro	synonymous	Exon 6 of 8	NP_000037.2
	ARSB	NM_198709.3		c.1191G>A	p.Pro397Pro	synonymous	Exon 7 of 8	NP_942002.1	P15848-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARSB	ENST00000264914.10	TSL:1 MANE Select	c.1191G>A	p.Pro397Pro	synonymous	Exon 6 of 8	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7	TSL:1	c.1191G>A	p.Pro397Pro	synonymous	Exon 7 of 8	ENSP00000379455.3	P15848-2
ARSB	ENST00000934338.1		c.1164G>A	p.Pro388Pro	synonymous	Exon 6 of 8	ENSP00000604397.1

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39800

AN:

151840

Hom.:

6979

Cov.:

show subpopulations

Gnomad AFR

AF:

0.501

Gnomad AMI

AF:

0.136

Gnomad AMR

AF:

0.173

Gnomad ASJ

AF:

0.270

Gnomad EAS

AF:

0.0416

Gnomad SAS

AF:

0.215

Gnomad FIN

AF:

0.115

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.257

GnomAD2 exomes

AF:

0.190

AC:

47785

AN:

251354

AF XY:

0.191

show subpopulations

Gnomad AFR exome

AF:

0.519

Gnomad AMR exome

AF:

0.110

Gnomad ASJ exome

AF:

0.271

Gnomad EAS exome

AF:

0.0436

Gnomad FIN exome

AF:

0.120

Gnomad NFE exome

AF:

0.187

Gnomad OTH exome

AF:

0.200

GnomAD4 exome

AF:

0.185

AC:

269562

AN:

1460836

Hom.:

28451

Cov.:

AF XY:

0.186

AC XY:

135054

AN XY:

726770

show subpopulations

African (AFR)

AF:

0.518

AC:

17335

AN:

33446

American (AMR)

AF:

0.119

AC:

5306

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.271

AC:

7082

AN:

26108

East Asian (EAS)

AF:

0.0331

AC:

1314

AN:

39682

South Asian (SAS)

AF:

0.224

AC:

19304

AN:

86232

European-Finnish (FIN)

AF:

0.120

AC:

6420

AN:

53396

Middle Eastern (MID)

AF:

0.278

AC:

1599

AN:

5760

European-Non Finnish (NFE)

AF:

0.179

AC:

199274

AN:

1111170

Other (OTH)

AF:

0.198

AC:

11928

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

10674

21348

32022

42696

53370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7020

14040

21060

28080

35100

<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:

0.262

AC:

39870

AN:

151958

Hom.:

7001

Cov.:

AF XY:

0.257

AC XY:

19069

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.502

AC:

20779

AN:

41426

American (AMR)

AF:

0.173

AC:

2636

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.270

AC:

937

AN:

3472

East Asian (EAS)

AF:

0.0419

AC:

217

AN:

5180

South Asian (SAS)

AF:

0.215

AC:

1030

AN:

4792

European-Finnish (FIN)

AF:

0.115

AC:

1213

AN:

10564

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.181

AC:

12325

AN:

67946

Other (OTH)

AF:

0.255

AC:

536

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1351

2701

4052

5402

6753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.212

Hom.:

18485

Bravo

AF:

0.276

Asia WGS

AF:

0.157

AC:

547

AN:

3476

EpiCase

AF:

0.201

EpiControl

AF:

0.204

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucopolysaccharidosis type 6 (4)

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.4

(source)

DANN

Benign

0.38

PhyloP100

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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