rs223493

Variant names:

• chr4-102747187-T-G
• rs223493
• NM_005908.4:c.177+13531A>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+13531A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 148,908 control chromosomes in the GnomAD database, including 6,581 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 0.29 (6581 hom., cov: 30)
• Consequence: MANBA NM_005908.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.679
• Publications: 9 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

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.177+13531A>C		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.177+13531A>C		intron	N/A	ENSP00000495247.1	O00462
	MANBA	ENST00000642252.1		c.177+13531A>C		intron	N/A	ENSP00000495483.1	A0A2R8YEC9
	MANBA	ENST00000954426.1		c.177+13531A>C		intron	N/A	ENSP00000624485.1

Frequencies

GnomAD3 genomes AF: 0.290 AC: 43164 AN: 148798 Hom.: 6576 Cov.: 30

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.280

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

GnomAD4 genome AF: 0.290 AC: 43203 AN: 148908 Hom.: 6581 Cov.: 30 AF XY: 0.289 AC XY: 20981 AN XY: 72718

African (AFR) AF: 0.403 AC: 15708 AN: 38962

American (AMR) AF: 0.307 AC: 4609 AN: 15024

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 946 AN: 3462

East Asian (EAS) AF: 0.209 AC: 1077 AN: 5164

South Asian (SAS) AF: 0.156 AC: 751 AN: 4806

European-Finnish (FIN) AF: 0.288 AC: 3020 AN: 10496

Middle Eastern (MID) AF: 0.273 AC: 77 AN: 282

European-Non Finnish (NFE) AF: 0.240 AC: 16265 AN: 67736

Other (OTH) AF: 0.278 AC: 573 AN: 2064

Alfa AF: 0.281 Hom.: 780

Bravo AF: 0.299

Asia WGS AF: 0.179 AC: 621 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.5
DANN	Benign	0.69
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

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: rs223493;

hg19: chr4-103668344;