5-78777743-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000046.5(ARSB):c.*2654A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00903 in 150,384 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0090 (13 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARSB NM_000046.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.490

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-78777743-T-C is Benign according to our data. Variant chr5-78777743-T-C is described in ClinVar as [Benign]. Clinvar id is 907643.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00903 (1358/150384) while in subpopulation AFR AF= 0.0289 (1176/40760). AF 95% confidence interval is 0.0275. There are 13 homozygotes in gnomad4. There are 622 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSB	NM_000046.5	c.*2654A>G		3_prime_UTR_variant	8/8	ENST00000264914.10
ARSB	XM_011543390.2	c.*2654A>G		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSB	ENST00000264914.10	c.*2654A>G		3_prime_UTR_variant	8/8	1	NM_000046.5	P1

Frequencies

GnomAD3 genomes AF: 0.00896 AC: 1346 AN: 150276 Hom.: 11 Cov.: 29

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00494

Gnomad ASJ AF: 0.0214

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.00725

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 80 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 62

Gnomad4 AFR 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 genome AF: 0.00903 AC: 1358 AN: 150384 Hom.: 13 Cov.: 29 AF XY: 0.00848 AC XY: 622 AN XY: 73326

Gnomad4 AFR AF: 0.0289

Gnomad4 AMR AF: 0.00493

Gnomad4 ASJ AF: 0.0214

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.00718

Alfa AF: 0.000351 Hom.: 0

Bravo AF: 0.00995

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.8
Dann	Benign	0.53

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: rs147170505; hg19: chr5-78073566;