rs228611

Variant names:

• chr4-102640552-G-A
• rs228611
• NM_005908.4:c.1870-695C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005908.4(MANBA):​c.1870-695C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 151,894 control chromosomes in the GnomAD database, including 13,361 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (13361 hom., cov: 31)
• Consequence: MANBA NM_005908.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311
• Publications: 28 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBA	NM_005908.4	c.1870-695C>T		intron_variant	Intron 13 of 16	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.1795-695C>T		intron_variant	Intron 14 of 17		XP_047271648.1
MANBA	XM_047415693.1	c.1795-695C>T		intron_variant	Intron 14 of 17		XP_047271649.1
MANBA	XM_047415694.1	c.1222-695C>T		intron_variant	Intron 9 of 12		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2	c.1870-695C>T		intron_variant	Intron 13 of 16		NM_005908.4	ENSP00000495247.1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61372 AN: 151778 Hom.: 13350 Cov.: 31

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.398

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

GnomAD4 genome AF: 0.404 AC: 61403 AN: 151894 Hom.: 13361 Cov.: 31 AF XY: 0.407 AC XY: 30180 AN XY: 74222

African (AFR) AF: 0.249 AC: 10307 AN: 41426

American (AMR) AF: 0.351 AC: 5359 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1625 AN: 3468

East Asian (EAS) AF: 0.491 AC: 2535 AN: 5168

South Asian (SAS) AF: 0.554 AC: 2665 AN: 4808

European-Finnish (FIN) AF: 0.509 AC: 5345 AN: 10510

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32239 AN: 67944

Other (OTH) AF: 0.405 AC: 852 AN: 2106

Alfa AF: 0.457 Hom.: 8453

Bravo AF: 0.381

Asia WGS AF: 0.485 AC: 1690 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.1
DANN	Benign	0.82
PhyloP100		-0.31
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: rs228611; hg19: chr4-103561709;