chr5-78777422-C-A

Variant names:

• chr5-78777422-C-A
• rs3088247
• NM_000046.5:c.*2975G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000046.5(ARSB):​c.*2975G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 152,444 control chromosomes in the GnomAD database, including 49,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (49090 hom., cov: 31)
  • Exomes 𝑓: 0.75 (120 hom.)
• Consequence: ARSB NM_000046.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.206

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 5-78777422-C-A is Benign according to our data. Variant chr5-78777422-C-A is described in ClinVar as [Benign]. Clinvar id is 354262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.*2975G>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000264914.10	NP_000037.2
ARSB	XM_011543390.2	c.*2975G>T		3_prime_UTR_variant	Exon 9 of 9		XP_011541692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914	c.*2975G>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_000046.5	ENSP00000264914.4

Frequencies

GnomAD3 genomes AF: 0.797 AC: 121027 AN: 151894 Hom.: 49043 Cov.: 31

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.785

Gnomad ASJ AF: 0.821

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.738

Gnomad MID AF: 0.745

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.765

GnomAD4 exome AF: 0.745 AC: 322 AN: 432 Hom.: 120 Cov.: 0 AF XY: 0.746 AC XY: 194 AN XY: 260

Gnomad4 FIN exome AF: 0.742

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.797 AC: 121122 AN: 152012 Hom.: 49090 Cov.: 31 AF XY: 0.791 AC XY: 58764 AN XY: 74284

Gnomad4 AFR AF: 0.940

Gnomad4 AMR AF: 0.784

Gnomad4 ASJ AF: 0.821

Gnomad4 EAS AF: 0.581

Gnomad4 SAS AF: 0.561

Gnomad4 FIN AF: 0.738

Gnomad4 NFE AF: 0.756

Gnomad4 OTH AF: 0.765

Alfa AF: 0.756 Hom.: 12847

Bravo AF: 0.808

Asia WGS AF: 0.561 AC: 1951 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.38
DANN	Benign	0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3088247; hg19: chr5-78073245; COSMIC: COSV53722226; COSMIC: COSV53722226;