chr4-102634907-G-T

Variant names:

• chr4-102634907-G-T
• rs147428514
• NM_005908.4:c.2296C>A
• MANBA p.Arg766Arg

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_005908.4(MANBA):​c.2296C>A​(p.Arg766Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. R766R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MANBA NM_005908.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.93
• Publications: 3 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, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 4-102634907-G-T is Benign according to our data. Variant chr4-102634907-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2855088.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.92 with no splicing effect.

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.2296C>A	p.Arg766Arg	synonymous	Exon 16 of 17	NP_005899.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	ENST00000647097.2	MANE Select	c.2296C>A	p.Arg766Arg	synonymous	Exon 16 of 17	ENSP00000495247.1	O00462
	MANBA	ENST00000642252.1		c.2434C>A	p.Arg812Arg	synonymous	Exon 17 of 18	ENSP00000495483.1	A0A2R8YEC9
	MANBA	ENST00000954426.1		c.2395C>A	p.Arg799Arg	synonymous	Exon 17 of 18	ENSP00000624485.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.9
DANN	Benign	0.37
PhyloP100		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs147428514;

hg19: chr4-103556064;