4-102631673-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005908.4(MANBA):c.*384C>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 0.525 in 470,540 control chromosomes in the GnomAD database, including 66,160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.55 (23357 hom., cov: 31)
  • Exomes 𝑓: 0.51 (42803 hom.)
• Consequence: MANBA NM_005908.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.118

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 4-102631673-G-A is Benign according to our data. Variant chr4-102631673-G-A is described in ClinVar as [Benign]. Clinvar id is 347068.Status of the report is criteria_provided_single_submitter, 1 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.*384C>T		3_prime_UTR_variant	17/17	ENST00000647097.2
MANBA	XM_047415692.1	c.*384C>T		3_prime_UTR_variant	18/18
MANBA	XM_047415693.1	c.*384C>T		3_prime_UTR_variant	18/18
MANBA	XM_047415694.1	c.*384C>T		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MANBA	ENST00000647097.2	c.*384C>T		3_prime_UTR_variant	17/17		NM_005908.4	P1

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83374 AN: 151640 Hom.: 23320 Cov.: 31

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.556

GnomAD4 exome AF: 0.513 AC: 163620 AN: 318782 Hom.: 42803 Cov.: 0 AF XY: 0.512 AC XY: 83033 AN XY: 162304

Gnomad4 AFR exome AF: 0.624

Gnomad4 AMR exome AF: 0.677

Gnomad4 ASJ exome AF: 0.491

Gnomad4 EAS exome AF: 0.482

Gnomad4 SAS exome AF: 0.451

Gnomad4 FIN exome AF: 0.472

Gnomad4 NFE exome AF: 0.510

Gnomad4 OTH exome AF: 0.538

GnomAD4 genome AF: 0.550 AC: 83458 AN: 151758 Hom.: 23357 Cov.: 31 AF XY: 0.549 AC XY: 40687 AN XY: 74136

Gnomad4 AFR AF: 0.632

Gnomad4 AMR AF: 0.616

Gnomad4 ASJ AF: 0.509

Gnomad4 EAS AF: 0.519

Gnomad4 SAS AF: 0.451

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.508

Gnomad4 OTH AF: 0.549

Alfa AF: 0.538 Hom.: 8636

Bravo AF: 0.567

Asia WGS AF: 0.506 AC: 1754 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beta-D-mannosidosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.95
Cadd	Benign	1.1
Dann	Benign	0.76

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4019; hg19: chr4-103552830; COSMIC: COSV105051650; COSMIC: COSV105051650;