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: Genomics England PanelApp, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

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 VariationId is 542168.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005908.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	NM_005908.4	MANE Select	c.2416-9delC		intron	N/A	NP_005899.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	ENST00000647097.2	MANE Select	c.2416-9delC		intron	N/A	ENSP00000495247.1	O00462
	MANBA	ENST00000642252.1		c.2554-9delC		intron	N/A	ENSP00000495483.1	A0A2R8YEC9
	MANBA	ENST00000954426.1		c.2515-9delC		intron	N/A	ENSP00000624485.1

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), 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), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000590 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Beta-D-mannosidosis (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1345228065;

hg19: chr4-103553446;