rs17033168

Positions:

• chr4-102690614-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005908.4(MANBA):​c.831A>G​(p.Leu277=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00845 in 1,611,444 control chromosomes in the GnomAD database, including 779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (406 hom., cov: 31)
  • Exomes 𝑓: 0.0052 (373 hom.)
• Consequence: MANBA NM_005908.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.23

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-102690614-T-C is Benign according to our data. Variant chr4-102690614-T-C is described in ClinVar as [Benign]. Clinvar id is 347095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANBA	NM_005908.4	c.831A>G	p.Leu277=	synonymous_variant	6/17	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.756A>G	p.Leu252=	synonymous_variant	7/18		XP_047271648.1
MANBA	XM_047415693.1	c.756A>G	p.Leu252=	synonymous_variant	7/18		XP_047271649.1
MANBA	XM_047415694.1	c.183A>G	p.Leu61=	synonymous_variant	2/13		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2	c.831A>G	p.Leu277=	synonymous_variant	6/17		NM_005908.4	ENSP00000495247	P1

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6030 AN: 152000 Hom.: 400 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0121 AC: 3033 AN: 251104 Hom.: 163 AF XY: 0.00947 AC XY: 1285 AN XY: 135704

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.00845

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.00693

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00849

GnomAD4 exome AF: 0.00518 AC: 7562 AN: 1459326 Hom.: 373 Cov.: 30 AF XY: 0.00481 AC XY: 3492 AN XY: 726114

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.000303

Gnomad4 SAS exome AF: 0.00746

Gnomad4 FIN exome AF: 0.0000939

Gnomad4 NFE exome AF: 0.000913

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0398 AC: 6054 AN: 152118 Hom.: 406 Cov.: 31 AF XY: 0.0386 AC XY: 2873 AN XY: 74356

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0109 Hom.: 128

Bravo AF: 0.0456

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00202

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2019	- -

Beta-D-mannosidosis Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.37
DANN	Benign	0.51

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: rs17033168; hg19: chr4-103611771;