NM_005908.4:c.2368T>A

Variant names:

• chr4-102634835-A-T
• rs2272697
• NM_005908.4:c.2368T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005908.4(MANBA):​c.2368T>A​(p.Leu790Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L790L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MANBA NM_005908.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.00
• Publications: 38 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBA	NM_005908.4	c.2368T>A	p.Leu790Met	missense_variant	Exon 16 of 17	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.2293T>A	p.Leu765Met	missense_variant	Exon 17 of 18		XP_047271648.1
MANBA	XM_047415693.1	c.2293T>A	p.Leu765Met	missense_variant	Exon 17 of 18		XP_047271649.1
MANBA	XM_047415694.1	c.1720T>A	p.Leu574Met	missense_variant	Exon 12 of 13		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2	c.2368T>A	p.Leu790Met	missense_variant	Exon 16 of 17		NM_005908.4	ENSP00000495247.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;D;D;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;.;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.68	D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.1	.;M;M;.;.
PhyloP100		3.0
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.83	.;N;.;.;N
REVEL	Benign	0.27
Sift	Benign	0.10	.;T;.;.;T
Sift4G	Benign	0.20	.;T;.;.;T
Polyphen		1.0, 1.0	.;D;D;.;D
Vest4		0.60, 0.63
MutPred		0.53		Gain of disorder (P = 0.0745);Gain of disorder (P = 0.0745);Gain of disorder (P = 0.0745);.;.;
MVP		0.31
MPC		0.43
ClinPred		0.87	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.32
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs2272697; hg19: chr4-103555992; COSMIC: COSV99899362; COSMIC: COSV99899362;