rs121434335

Variant names:

• chr4-102726614-C-A
• rs121434335
• NM_005908.4:c.247G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-102726614-C-A
• chr4-102726614-C-G
• chr4-102726614-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005908.4(MANBA):​c.247G>T​(p.Glu83*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E83E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MANBA NM_005908.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.217
• Publications: 6 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: Ambry Genetics, Orphanet, G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-102726614-C-A is Pathogenic according to our data. Variant chr4-102726614-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1681.Status of the report is no_assertion_criteria_provided, 0 stars.

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.247G>T	p.Glu83*	stop_gained	Exon 2 of 17	NP_005899.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	ENST00000647097.2	MANE Select	c.247G>T	p.Glu83*	stop_gained	Exon 2 of 17	ENSP00000495247.1	O00462
	MANBA	ENST00000642252.1		c.247G>T	p.Glu83*	stop_gained	Exon 2 of 18	ENSP00000495483.1	A0A2R8YEC9
	MANBA	ENST00000954426.1		c.247G>T	p.Glu83*	stop_gained	Exon 2 of 18	ENSP00000624485.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399318 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 699108

African (AFR) AF: 0.00 AC: 0 AN: 32088

American (AMR) AF: 0.00 AC: 0 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25730

East Asian (EAS) AF: 0.00 AC: 0 AN: 39252

South Asian (SAS) AF: 0.00 AC: 0 AN: 84086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 9.47e-7 AC: 1 AN: 1056466

Other (OTH) AF: 0.00 AC: 0 AN: 58412

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Beta-D-mannosidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Benign	-0.0091
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.13	N
PhyloP100		0.22
Vest4		0.83
GERP RS		1.5
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121434335; hg19: chr4-103647771; COSMIC: COSV99898471; COSMIC: COSV99898471;