rs2272697

Positions:

• chr4-102634835-A-G
• chr4-102634835-A-T

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.2368T>C​(p.Leu790=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,613,786 control chromosomes in the GnomAD database, including 224,504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23406 hom., cov: 32)
  • Exomes 𝑓: 0.52 (201098 hom.)
• Consequence: MANBA NM_005908.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.00

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=-0.58).
• BP6: Variant 4-102634835-A-G is Benign according to our data. Variant chr4-102634835-A-G is described in ClinVar as [Benign]. Clinvar id is 95320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102634835-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MANBA	NM_005908.4	c.2368T>C	p.Leu790=	synonymous_variant	16/17	ENST00000647097.2
MANBA	XM_047415692.1	c.2293T>C	p.Leu765=	synonymous_variant	17/18
MANBA	XM_047415693.1	c.2293T>C	p.Leu765=	synonymous_variant	17/18
MANBA	XM_047415694.1	c.1720T>C	p.Leu574=	synonymous_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MANBA	ENST00000647097.2	c.2368T>C	p.Leu790=	synonymous_variant	16/17		NM_005908.4	P1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83484 AN: 151954 Hom.: 23368 Cov.: 32

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.618

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.471

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.556

GnomAD3 exomes AF: 0.541 AC: 135905 AN: 251324 Hom.: 37947 AF XY: 0.529 AC XY: 71883 AN XY: 135828

Gnomad AFR exome AF: 0.635

Gnomad AMR exome AF: 0.735

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.529

Gnomad SAS exome AF: 0.455

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.508

Gnomad OTH exome AF: 0.533

GnomAD4 exome AF: 0.521 AC: 762192 AN: 1461714 Hom.: 201098 Cov.: 60 AF XY: 0.518 AC XY: 376758 AN XY: 727158

Gnomad4 AFR exome AF: 0.634

Gnomad4 AMR exome AF: 0.724

Gnomad4 ASJ exome AF: 0.493

Gnomad4 EAS exome AF: 0.493

Gnomad4 SAS exome AF: 0.461

Gnomad4 FIN exome AF: 0.476

Gnomad4 NFE exome AF: 0.518

Gnomad4 OTH exome AF: 0.532

GnomAD4 genome AF: 0.550 AC: 83569 AN: 152072 Hom.: 23406 Cov.: 32 AF XY: 0.548 AC XY: 40779 AN XY: 74348

Gnomad4 AFR AF: 0.631

Gnomad4 AMR AF: 0.618

Gnomad4 ASJ AF: 0.508

Gnomad4 EAS AF: 0.517

Gnomad4 SAS AF: 0.451

Gnomad4 FIN AF: 0.471

Gnomad4 NFE AF: 0.508

Gnomad4 OTH AF: 0.549

Alfa AF: 0.522 Hom.: 26597

Bravo AF: 0.567

Asia WGS AF: 0.505 AC: 1753 AN: 3478

EpiCase AF: 0.516

EpiControl AF: 0.504

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2013	- -

Beta-D-mannosidosis Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.6
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2272697; hg19: chr4-103555992; COSMIC: COSV56964471; COSMIC: COSV56964471;