4-102631933-A-G

Variant summary

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

The NM_005908.4(MANBA):c.*124T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 841,964 control chromosomes in the GnomAD database, including 117,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23420 hom., cov: 33)
  • Exomes 𝑓: 0.52 (93665 hom.)
• Consequence: MANBA NM_005908.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.313

Genes affected

MANBA (HGNC:6831): (mannosidase beta) This gene encodes a member of the glycosyl hydrolase 2 family. The encoded protein localizes to the lysosome where it is the final exoglycosidase in the pathway for N-linked glycoprotein oligosaccharide catabolism. Mutations in this gene are associated with beta-mannosidosis, a lysosomal storage disease that has a wide spectrum of neurological involvement. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 4-102631933-A-G is Benign according to our data. Variant chr4-102631933-A-G is described in ClinVar as [Benign]. Clinvar id is 347075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MANBA	NM_005908.4	c.*124T>C		3_prime_UTR_variant	17/17	ENST00000647097.2
MANBA	XM_047415692.1	c.*124T>C		3_prime_UTR_variant	18/18
MANBA	XM_047415693.1	c.*124T>C		3_prime_UTR_variant	18/18
MANBA	XM_047415694.1	c.*124T>C		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MANBA	ENST00000647097.2	c.*124T>C		3_prime_UTR_variant	17/17		NM_005908.4	P1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83524 AN: 152070 Hom.: 23383 Cov.: 33

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.615

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.555

GnomAD4 exome AF: 0.517 AC: 356453 AN: 689776 Hom.: 93665 Cov.: 9 AF XY: 0.512 AC XY: 187687 AN XY: 366416

Gnomad4 AFR exome AF: 0.627

Gnomad4 AMR exome AF: 0.715

Gnomad4 ASJ exome AF: 0.492

Gnomad4 EAS exome AF: 0.489

Gnomad4 SAS exome AF: 0.461

Gnomad4 FIN exome AF: 0.476

Gnomad4 NFE exome AF: 0.510

Gnomad4 OTH exome AF: 0.533

GnomAD4 genome AF: 0.549 AC: 83608 AN: 152188 Hom.: 23420 Cov.: 33 AF XY: 0.548 AC XY: 40781 AN XY: 74418

Gnomad4 AFR AF: 0.631

Gnomad4 AMR AF: 0.615

Gnomad4 ASJ AF: 0.508

Gnomad4 EAS AF: 0.517

Gnomad4 SAS AF: 0.452

Gnomad4 FIN AF: 0.471

Gnomad4 NFE AF: 0.508

Gnomad4 OTH AF: 0.548

Alfa AF: 0.538 Hom.: 8567

Bravo AF: 0.567

Asia WGS AF: 0.505 AC: 1753 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

- -

Beta-D-mannosidosis 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	-0.96
Cadd	Benign	4.0
Dann	Benign	0.37
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: rs3194585; hg19: chr4-103553090;