rs227368

Positions:

• chr4-102690688-C-A
• chr4-102690688-C-G
• chr4-102690688-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005908.4(MANBA):​c.757G>T​(p.Val253Leu) variant causes a missense 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V253I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MANBA NM_005908.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.114

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07795921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANBA	NM_005908.4	c.757G>T	p.Val253Leu	missense_variant	6/17	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.682G>T	p.Val228Leu	missense_variant	7/18		XP_047271648.1
MANBA	XM_047415693.1	c.682G>T	p.Val228Leu	missense_variant	7/18		XP_047271649.1
MANBA	XM_047415694.1	c.109G>T	p.Val37Leu	missense_variant	2/13		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2	c.757G>T	p.Val253Leu	missense_variant	6/17		NM_005908.4	ENSP00000495247	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.91
DANN	Benign	0.94
DEOGEN2	Benign	0.35	.;T;T;.;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.82	T;.;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.078	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.0	.;M;M;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	.;N;.;.;N
REVEL	Benign	0.046
Sift	Benign	0.14	.;T;.;.;T
Sift4G	Benign	0.38	.;T;.;.;T
Polyphen		0.0030, 0.040	.;B;B;.;B
Vest4		0.33, 0.32
MutPred		0.20		Loss of glycosylation at P256 (P = 0.0794);Loss of glycosylation at P256 (P = 0.0794);Loss of glycosylation at P256 (P = 0.0794);Loss of glycosylation at P256 (P = 0.0794);.;
MVP		0.36
MPC		0.076
ClinPred		0.16	T
GERP RS		1.3
Varity_R		0.040
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs227368; hg19: chr4-103611845;