Genetic Variant MANBA:c.2416-11_2416-10delTT (chr4-102632290-GAA-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS1

The NM_005908.4(MANBA):c.2416-11_2416-10delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,389,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00075 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

MANBA
NM_005908.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.248

Publications

3 publications found

Variant links:

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

MANBA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 4-102632290-GAA-G is Benign according to our data. Variant chr4-102632290-GAA-G is described in ClinVar as Benign. ClinVar VariationId is 1639188.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000748 (111/148450) while in subpopulation AFR AF = 0.00251 (102/40718). AF 95% confidence interval is 0.00211. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.2416-11_2416-10delTT		intron	N/A	NP_005899.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MANBA	ENST00000647097.2	MANE Select	c.2416-11_2416-10delTT	intron	N/A	ENSP00000495247.1	O00462
MANBA	ENST00000642252.1		c.2554-11_2554-10delTT	intron	N/A	ENSP00000495483.1	A0A2R8YEC9
MANBA	ENST00000954426.1		c.2515-11_2515-10delTT	intron	N/A	ENSP00000624485.1

Frequencies

GnomAD3 genomes

AF:

0.000742

AC:

110

AN:

148344

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000333

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000450

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000419

AC:

AN:

205224

AF XY:

0.000405

show subpopulations

Gnomad AFR exome

AF:

0.00270

Gnomad AMR exome

AF:

0.000197

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000456

Gnomad FIN exome

AF:

0.0000565

Gnomad NFE exome

AF:

0.000309

Gnomad OTH exome

AF:

0.000200

GnomAD4 exome

AF:

0.000328

AC:

407

AN:

1240772

Hom.:

AF XY:

0.000305

AC XY:

190

AN XY:

622834

show subpopulations

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

African (AFR)

AF:

0.00225

AC:

AN:

28450

American (AMR)

AF:

0.000169

AC:

AN:

41444

Ashkenazi Jewish (ASJ)

AF:

0.0000429

AC:

AN:

23292

East Asian (EAS)

AF:

0.000337

AC:

AN:

35638

South Asian (SAS)

AF:

0.000271

AC:

AN:

77522

European-Finnish (FIN)

AF:

0.0000412

AC:

AN:

48492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5212

European-Non Finnish (NFE)

AF:

0.000306

AC:

284

AN:

928668

Other (OTH)

AF:

0.000307

AC:

AN:

52054

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000748

AC:

111

AN:

148450

Hom.:

Cov.:

AF XY:

0.000775

AC XY:

AN XY:

72282

show subpopulations

African (AFR)

AF:

0.00251

AC:

102

AN:

40718

American (AMR)

AF:

0.000333

AC:

AN:

15020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3420

East Asian (EAS)

AF:

0.000199

AC:

AN:

5028

South Asian (SAS)

AF:

0.00

AC:

AN:

4666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

66630

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000258

Hom.:

1436

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Beta-D-mannosidosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.25

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over