rs227368

Variant names:

• chr4-102690688-C-A
• rs227368
• NM_005908.4:c.757G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V253I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MANBA NM_005908.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.114
• Publications: 55 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 0 ACMG points.

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	NM_005908.4	MANE Select	c.757G>T	p.Val253Leu	missense	Exon 6 of 17	NP_005899.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	ENST00000647097.2	MANE Select	c.757G>T	p.Val253Leu	missense	Exon 6 of 17	ENSP00000495247.1
	MANBA	ENST00000642252.1		c.757G>T	p.Val253Leu	missense	Exon 6 of 18	ENSP00000495483.1
	MANBA	ENST00000644159.1		c.757G>T	p.Val253Leu	missense	Exon 6 of 18	ENSP00000494462.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.11
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.046
Sift	Benign	0.14	T
Sift4G	Benign	0.38	T
Polyphen		0.0030	B
Vest4		0.33
MutPred		0.20		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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs227368; hg19: chr4-103611845;