4-102631701-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005908.4(MANBA):c.*356G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0424 in 531,228 control chromosomes in the GnomAD database, including 491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.043 (150 hom., cov: 32)
  • Exomes 𝑓: 0.042 (341 hom.)
• Consequence: MANBA NM_005908.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.517

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-102631701-C-T is Benign according to our data. Variant chr4-102631701-C-T is described in ClinVar as [Benign]. Clinvar id is 347069.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-102631701-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0431 (6561/152238) while in subpopulation EAS AF= 0.0548 (284/5180). AF 95% confidence interval is 0.0496. There are 150 homozygotes in gnomad4. There are 3220 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 149 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MANBA	NM_005908.4	c.*356G>A		3_prime_UTR_variant	17/17	ENST00000647097.2
MANBA	XM_047415692.1	c.*356G>A		3_prime_UTR_variant	18/18
MANBA	XM_047415693.1	c.*356G>A		3_prime_UTR_variant	18/18
MANBA	XM_047415694.1	c.*356G>A		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MANBA	ENST00000647097.2	c.*356G>A		3_prime_UTR_variant	17/17		NM_005908.4	P1

Frequencies

GnomAD3 genomes AF: 0.0431 AC: 6554 AN: 152120 Hom.: 149 Cov.: 32

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0551

Gnomad SAS AF: 0.0409

Gnomad FIN AF: 0.0622

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.0383

GnomAD4 exome AF: 0.0421 AC: 15950 AN: 378990 Hom.: 341 Cov.: 0 AF XY: 0.0413 AC XY: 8082 AN XY: 195604

Gnomad4 AFR exome AF: 0.0332

Gnomad4 AMR exome AF: 0.0229

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.0470

Gnomad4 SAS exome AF: 0.0321

Gnomad4 FIN exome AF: 0.0557

Gnomad4 NFE exome AF: 0.0442

Gnomad4 OTH exome AF: 0.0424

GnomAD4 genome AF: 0.0431 AC: 6561 AN: 152238 Hom.: 150 Cov.: 32 AF XY: 0.0433 AC XY: 3220 AN XY: 74438

Gnomad4 AFR AF: 0.0394

Gnomad4 AMR AF: 0.0317

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.0548

Gnomad4 SAS AF: 0.0415

Gnomad4 FIN AF: 0.0622

Gnomad4 NFE AF: 0.0457

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0389 Hom.: 136

Bravo AF: 0.0410

Asia WGS AF: 0.0480 AC: 168 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beta-D-mannosidosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	6.0
Dann	Benign	0.75

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7672268; hg19: chr4-103552858;