4-102631740-T-C

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.*317A>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 0.015 in 570,402 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (143 hom., cov: 32)
  • Exomes 𝑓: 0.010 (62 hom.)
• Consequence: MANBA NM_005908.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.489

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=-0.97).
• BP6: Variant 4-102631740-T-C is Benign according to our data. Variant chr4-102631740-T-C is described in ClinVar as [Benign]. Clinvar id is 347070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MANBA	NM_005908.4	c.*317A>G		3_prime_UTR_variant	17/17	ENST00000647097.2
MANBA	XM_047415692.1	c.*317A>G		3_prime_UTR_variant	18/18
MANBA	XM_047415693.1	c.*317A>G		3_prime_UTR_variant	18/18
MANBA	XM_047415694.1	c.*317A>G		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MANBA	ENST00000647097.2	c.*317A>G		3_prime_UTR_variant	17/17		NM_005908.4	P1

Frequencies

GnomAD3 genomes AF: 0.0283 AC: 4303 AN: 152192 Hom.: 139 Cov.: 32

Gnomad AFR AF: 0.0792

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.0101 AC: 4202 AN: 418092 Hom.: 62 Cov.: 0 AF XY: 0.00923 AC XY: 2013 AN XY: 218194

Gnomad4 AFR exome AF: 0.0776

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.00120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000636

Gnomad4 FIN exome AF: 0.00373

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0284 AC: 4326 AN: 152310 Hom.: 143 Cov.: 32 AF XY: 0.0272 AC XY: 2023 AN XY: 74494

Gnomad4 AFR AF: 0.0796

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00282

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0186 Hom.: 7

Bravo AF: 0.0315

Asia WGS AF: 0.00808 AC: 28 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

Mar 24, 2019

- -

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	-0.97
Cadd	Benign	5.1
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs78514870; hg19: chr4-103552897;