4-102634462-C-G

Variant names:

• chr4-102634462-C-G
• rs6813322
• NM_005908.4:c.2415+326G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005908.4(MANBA):​c.2415+326G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 151,638 control chromosomes in the GnomAD database, including 23,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.55 (23188 hom., cov: 32)
• Consequence: MANBA NM_005908.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.535
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• beta-mannosidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-102634462-C-G is Benign according to our data. Variant chr4-102634462-C-G is described in ClinVar as Benign. ClinVar VariationId is 667480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBA	NM_005908.4	c.2415+326G>C		intron_variant	Intron 16 of 16	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.2340+326G>C		intron_variant	Intron 17 of 17		XP_047271648.1
MANBA	XM_047415693.1	c.2340+326G>C		intron_variant	Intron 17 of 17		XP_047271649.1
MANBA	XM_047415694.1	c.1767+326G>C		intron_variant	Intron 12 of 12		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2	c.2415+326G>C		intron_variant	Intron 16 of 16		NM_005908.4	ENSP00000495247.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83051 AN: 151520 Hom.: 23150 Cov.: 32

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.507

Gnomad OTH AF: 0.554

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.548 AC: 83136 AN: 151638 Hom.: 23188 Cov.: 32 AF XY: 0.547 AC XY: 40516 AN XY: 74068

African (AFR) AF: 0.629 AC: 25976 AN: 41290

American (AMR) AF: 0.617 AC: 9409 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1757 AN: 3462

East Asian (EAS) AF: 0.514 AC: 2650 AN: 5152

South Asian (SAS) AF: 0.450 AC: 2163 AN: 4812

European-Finnish (FIN) AF: 0.470 AC: 4943 AN: 10518

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.507 AC: 34392 AN: 67852

Other (OTH) AF: 0.548 AC: 1152 AN: 2104

Alfa AF: 0.363 Hom.: 781

Bravo AF: 0.567

Asia WGS AF: 0.505 AC: 1753 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.0
DANN	Benign	0.61
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6813322; hg19: chr4-103555619;