4-102635920-G-T

Position:

• chr4-102635920-G-T

Variant summary

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

The NM_005908.4(MANBA):​c.2102C>A​(p.Thr701Lys) 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. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T701M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MANBA NM_005908.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82

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 (HGNC:):

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=0.046967447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANBA	NM_005908.4	c.2102C>A	p.Thr701Lys	missense_variant	15/17	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.2027C>A	p.Thr676Lys	missense_variant	16/18		XP_047271648.1
MANBA	XM_047415693.1	c.2027C>A	p.Thr676Lys	missense_variant	16/18		XP_047271649.1
MANBA	XM_047415694.1	c.1454C>A	p.Thr485Lys	missense_variant	11/13		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2	c.2102C>A	p.Thr701Lys	missense_variant	15/17		NM_005908.4	ENSP00000495247.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1457884 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 725510

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.6
DANN	Benign	0.22
DEOGEN2	Benign	0.21	.;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.52	T;.;T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.047	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	.;N;N;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	.;N;.;.;N
REVEL	Benign	0.080
Sift	Benign	0.88	.;T;.;.;T
Sift4G	Benign	0.93	.;T;.;.;T
Polyphen		0.0050, 0.025	.;B;B;.;B
Vest4		0.17, 0.17
MutPred		0.47		Gain of methylation at T701 (P = 0.0068);Gain of methylation at T701 (P = 0.0068);Gain of methylation at T701 (P = 0.0068);.;.;
MVP		0.18
MPC		0.092
ClinPred		0.033	T
GERP RS		2.8
Varity_R		0.040
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2866413; hg19: chr4-103557077;