4-102723925-C-T

Position:

• chr4-102723925-C-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.315G>A​(p.Thr105Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,610,210 control chromosomes in the GnomAD database, including 3,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (1778 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1868 hom.)
• Consequence: MANBA NM_005908.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.401

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]

MANBA (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 4-102723925-C-T is Benign according to our data. Variant chr4-102723925-C-T is described in ClinVar as [Benign]. Clinvar id is 347099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102723925-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.401 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANBA	NM_005908.4	c.315G>A	p.Thr105Thr	synonymous_variant	3/17	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.240G>A	p.Thr80Thr	synonymous_variant	4/18		XP_047271648.1
MANBA	XM_047415693.1	c.240G>A	p.Thr80Thr	synonymous_variant	4/18		XP_047271649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2	c.315G>A	p.Thr105Thr	synonymous_variant	3/17		NM_005908.4	ENSP00000495247.1

Frequencies

GnomAD3 genomes AF: 0.0932 AC: 14140 AN: 151764 Hom.: 1763 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0436

Gnomad ASJ AF: 0.00808

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.00703

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0727

GnomAD3 exomes AF: 0.0348 AC: 8712 AN: 250228 Hom.: 808 AF XY: 0.0296 AC XY: 3998 AN XY: 135220

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.0316

Gnomad ASJ exome AF: 0.00497

Gnomad EAS exome AF: 0.000545

Gnomad SAS exome AF: 0.0145

Gnomad FIN exome AF: 0.00791

Gnomad NFE exome AF: 0.0173

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0238 AC: 34643 AN: 1458328 Hom.: 1868 Cov.: 29 AF XY: 0.0226 AC XY: 16407 AN XY: 725682

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.0330

Gnomad4 ASJ exome AF: 0.00609

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.00738

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0351

GnomAD4 genome AF: 0.0935 AC: 14197 AN: 151882 Hom.: 1778 Cov.: 32 AF XY: 0.0909 AC XY: 6745 AN XY: 74228

Gnomad4 AFR AF: 0.290

Gnomad4 AMR AF: 0.0435

Gnomad4 ASJ AF: 0.00808

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0158

Gnomad4 FIN AF: 0.00703

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0715

Alfa AF: 0.0424 Hom.: 674

Bravo AF: 0.105

Asia WGS AF: 0.0330 AC: 116 AN: 3474

EpiCase AF: 0.0182

EpiControl AF: 0.0183

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2017	- -

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	-0.69
CADD	Benign	8.9
DANN	Benign	0.72

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: rs6857760; hg19: chr4-103645082;