4-102632085-T-C

Position:

• chr4-102632085-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005908.4(MANBA):​c.2612A>G​(p.His871Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H871H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MANBA NM_005908.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.286

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066266626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MANBA	NM_005908.4	c.2612A>G	p.His871Arg	missense_variant	17/17	ENST00000647097.2
MANBA	XM_047415692.1	c.2537A>G	p.His846Arg	missense_variant	18/18
MANBA	XM_047415693.1	c.2537A>G	p.His846Arg	missense_variant	18/18
MANBA	XM_047415694.1	c.1964A>G	p.His655Arg	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MANBA	ENST00000647097.2	c.2612A>G	p.His871Arg	missense_variant	17/17		NM_005908.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456438 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.081
DANN	Benign	0.15
DEOGEN2	Benign	0.20	T;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.36	.;T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.066	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.47	N;N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.64	N;.;.;N
REVEL	Benign	0.035
Sift	Benign	0.72	T;.;.;T
Sift4G	Benign	0.65	T;.;.;T
Polyphen		0.0	B;B;.;B
Vest4		0.033
MVP		0.25
MPC		0.091
ClinPred		0.0092	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.019
gMVP		0.31

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: rs1729402934; hg19: chr4-103553242;