rs1345228065

Variant names:

• chr4-102632289-AG-A
• rs1345228065
• NM_005908.4:c.2416-9delC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_005908.4(MANBA):​c.2416-9delC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000096 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MANBA NM_005908.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.365
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 4-102632289-AG-A is Benign according to our data. Variant chr4-102632289-AG-A is described in ClinVar as [Likely_benign]. Clinvar id is 542168.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBA	NM_005908.4	c.2416-9delC		intron_variant	Intron 16 of 16	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.2341-9delC		intron_variant	Intron 17 of 17		XP_047271648.1
MANBA	XM_047415693.1	c.2341-9delC		intron_variant	Intron 17 of 17		XP_047271649.1
MANBA	XM_047415694.1	c.1768-9delC		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.2416-9delC		intron_variant	Intron 16 of 16		NM_005908.4	ENSP00000495247.1

Frequencies

GnomAD3 genomes AF: 0.00000963 AC: 1 AN: 103810 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000451 AC: 92 AN: 203856 AF XY: 0.000427

Gnomad AFR exome AF: 0.000934

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000451

Gnomad FIN exome AF: 0.000110

Gnomad NFE exome AF: 0.000401

Gnomad OTH exome AF: 0.000571

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000141 AC: 201 AN: 1428516 Hom.: 0 Cov.: 25 AF XY: 0.000135 AC XY: 96 AN XY: 712648

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000888 AC: 29 AN: 32646

American (AMR) AF: 0.00156 AC: 69 AN: 44238

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.000281 AC: 24 AN: 85470

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000591 AC: 64 AN: 1082390

Other (OTH) AF: 0.000152 AC: 9 AN: 59314

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000963 AC: 1 AN: 103810 Hom.: 0 Cov.: 29 AF XY: 0.0000198 AC XY: 1 AN XY: 50572

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24348

American (AMR) AF: 0.00 AC: 0 AN: 9060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2568

East Asian (EAS) AF: 0.00 AC: 0 AN: 3738

South Asian (SAS) AF: 0.00 AC: 0 AN: 3602

European-Finnish (FIN) AF: 0.000123 AC: 1 AN: 8120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 190

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 50172

Other (OTH) AF: 0.00 AC: 0 AN: 1414

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000590 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beta-D-mannosidosis Benign:1

Feb 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1345228065; hg19: chr4-103553446;