4-102759827-A-G

Variant names:

• chr4-102759827-A-G
• rs223489
• NM_005908.4:c.177+891T>C

Variant summary

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

The NM_005908.4(MANBA):​c.177+891T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 151,940 control chromosomes in the GnomAD database, including 12,064 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 (12064 hom., cov: 32)
• Consequence: MANBA NM_005908.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24
• Publications: 18 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBA	NM_005908.4	c.177+891T>C		intron_variant	Intron 1 of 16	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.-3368+891T>C		intron_variant	Intron 1 of 17		XP_047271648.1
MANBA	XM_047415693.1	c.-3368+497T>C		intron_variant	Intron 1 of 17		XP_047271649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2	c.177+891T>C		intron_variant	Intron 1 of 16		NM_005908.4	ENSP00000495247.1

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60186 AN: 151822 Hom.: 12051 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.450

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.411

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

GnomAD4 genome AF: 0.396 AC: 60235 AN: 151940 Hom.: 12064 Cov.: 32 AF XY: 0.400 AC XY: 29699 AN XY: 74286

African (AFR) AF: 0.442 AC: 18313 AN: 41390

American (AMR) AF: 0.451 AC: 6884 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1420 AN: 3468

East Asian (EAS) AF: 0.386 AC: 1999 AN: 5174

South Asian (SAS) AF: 0.368 AC: 1778 AN: 4828

European-Finnish (FIN) AF: 0.407 AC: 4290 AN: 10536

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24269 AN: 67964

Other (OTH) AF: 0.407 AC: 860 AN: 2112

Alfa AF: 0.378 Hom.: 13549

Bravo AF: 0.402

Asia WGS AF: 0.377 AC: 1311 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		2.2
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: rs223489; hg19: chr4-103680984;