4-102726614-C-T

Variant names:

• chr4-102726614-C-T
• rs121434335
• NM_005908.4:c.247G>A

Variant summary

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

The NM_005908.4(MANBA):​c.247G>A​(p.Glu83Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,318 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MANBA NM_005908.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.217

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=0.10639137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBA	NM_005908.4	c.247G>A	p.Glu83Lys	missense_variant	Exon 2 of 17	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.172G>A	p.Glu58Lys	missense_variant	Exon 3 of 18		XP_047271648.1
MANBA	XM_047415693.1	c.172G>A	p.Glu58Lys	missense_variant	Exon 3 of 18		XP_047271649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2	c.247G>A	p.Glu83Lys	missense_variant	Exon 2 of 17		NM_005908.4	ENSP00000495247.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249606 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399318 Hom.: 0 Cov.: 28 AF XY: 0.00000143 AC XY: 1 AN XY: 699108

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.74
DEOGEN2	Benign	0.24	.;T;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.80	T;.;T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.86	.;L;L;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.93	.;N;.;.;N;.
REVEL	Benign	0.057
Sift	Benign	0.55	.;T;.;.;T;.
Sift4G	Benign	0.81	.;T;.;.;T;.
Polyphen		0.0010, 0.0020	.;B;B;.;B;.
Vest4		0.19, 0.19
MutPred		0.53		Gain of methylation at E83 (P = 0.0092);Gain of methylation at E83 (P = 0.0092);Gain of methylation at E83 (P = 0.0092);Gain of methylation at E83 (P = 0.0092);Gain of methylation at E83 (P = 0.0092);.;
MVP		0.29
MPC		0.087
ClinPred		0.016	T
GERP RS		1.5
Varity_R		0.040
gMVP		0.43

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: rs121434335; hg19: chr4-103647771;