chr4-102690614-T-C

Variant names:

• chr4-102690614-T-C
• rs17033168
• NM_005908.4:c.831A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005908.4(MANBA):​c.831A>G​(p.Leu277Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00845 in 1,611,444 control chromosomes in the GnomAD database, including 779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (406 hom., cov: 31)
  • Exomes 𝑓: 0.0052 (373 hom.)
• Consequence: MANBA NM_005908.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.23
• Publications: 2 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: Ambry Genetics, Orphanet, G2P, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-102690614-T-C is Benign according to our data. Variant chr4-102690614-T-C is described in ClinVar as Benign. ClinVar VariationId is 347095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	NM_005908.4	MANE Select	c.831A>G	p.Leu277Leu	synonymous	Exon 6 of 17	NP_005899.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	ENST00000647097.2	MANE Select	c.831A>G	p.Leu277Leu	synonymous	Exon 6 of 17	ENSP00000495247.1	O00462
	MANBA	ENST00000642252.1		c.831A>G	p.Leu277Leu	synonymous	Exon 6 of 18	ENSP00000495483.1	A0A2R8YEC9
	MANBA	ENST00000954426.1		c.831A>G	p.Leu277Leu	synonymous	Exon 6 of 18	ENSP00000624485.1

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6030 AN: 152000 Hom.: 400 Cov.: 31

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.0316

GnomAD2 exomes AF: 0.0121 AC: 3033 AN: 251104 AF XY: 0.00947

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.00845

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00849

GnomAD4 exome AF: 0.00518 AC: 7562 AN: 1459326 Hom.: 373 Cov.: 30 AF XY: 0.00481 AC XY: 3492 AN XY: 726114

African (AFR) AF: 0.138 AC: 4595 AN: 33340

American (AMR) AF: 0.0103 AC: 461 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26050

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39540

South Asian (SAS) AF: 0.00746 AC: 643 AN: 86202

European-Finnish (FIN) AF: 0.0000939 AC: 5 AN: 53256

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5740

European-Non Finnish (NFE) AF: 0.000913 AC: 1014 AN: 1110348

Other (OTH) AF: 0.0121 AC: 730 AN: 60188

GnomAD4 genome AF: 0.0398 AC: 6054 AN: 152118 Hom.: 406 Cov.: 31 AF XY: 0.0386 AC XY: 2873 AN XY: 74356

African (AFR) AF: 0.135 AC: 5598 AN: 41504

American (AMR) AF: 0.0180 AC: 275 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4824

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 67986

Other (OTH) AF: 0.0313 AC: 66 AN: 2112

Alfa AF: 0.0214 Hom.: 405

Bravo AF: 0.0456

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Beta-D-mannosidosis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.37
DANN	Benign	0.51
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs17033168; hg19: chr4-103611771;