NM_005908.4:c.315G>A

Variant names:

• chr4-102723925-C-T
• rs6857760
• NM_005908.4:c.315G>A

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.315G>A​(p.Thr105Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,610,210 control chromosomes in the GnomAD database, including 3,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (1778 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1868 hom.)
• Consequence: MANBA NM_005908.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.401
• Publications: 5 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=-0.69).
• BP6: Variant 4-102723925-C-T is Benign according to our data. Variant chr4-102723925-C-T is described in ClinVar as Benign. ClinVar VariationId is 347099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.401 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 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.315G>A	p.Thr105Thr	synonymous	Exon 3 of 17	NP_005899.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	ENST00000647097.2	MANE Select	c.315G>A	p.Thr105Thr	synonymous	Exon 3 of 17	ENSP00000495247.1	O00462
	MANBA	ENST00000642252.1		c.315G>A	p.Thr105Thr	synonymous	Exon 3 of 18	ENSP00000495483.1	A0A2R8YEC9
	MANBA	ENST00000954426.1		c.315G>A	p.Thr105Thr	synonymous	Exon 3 of 18	ENSP00000624485.1

Frequencies

GnomAD3 genomes AF: 0.0932 AC: 14140 AN: 151764 Hom.: 1763 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0436

Gnomad ASJ AF: 0.00808

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.00703

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0727

GnomAD2 exomes AF: 0.0348 AC: 8712 AN: 250228 AF XY: 0.0296

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.0316

Gnomad ASJ exome AF: 0.00497

Gnomad EAS exome AF: 0.000545

Gnomad FIN exome AF: 0.00791

Gnomad NFE exome AF: 0.0173

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0238 AC: 34643 AN: 1458328 Hom.: 1868 Cov.: 29 AF XY: 0.0226 AC XY: 16407 AN XY: 725682

African (AFR) AF: 0.296 AC: 9831 AN: 33186

American (AMR) AF: 0.0330 AC: 1472 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00609 AC: 159 AN: 26110

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39574

South Asian (SAS) AF: 0.0164 AC: 1408 AN: 85894

European-Finnish (FIN) AF: 0.00738 AC: 394 AN: 53390

Middle Eastern (MID) AF: 0.0452 AC: 260 AN: 5758

European-Non Finnish (NFE) AF: 0.0171 AC: 18991 AN: 1109482

Other (OTH) AF: 0.0351 AC: 2115 AN: 60284

GnomAD4 genome AF: 0.0935 AC: 14197 AN: 151882 Hom.: 1778 Cov.: 32 AF XY: 0.0909 AC XY: 6745 AN XY: 74228

African (AFR) AF: 0.290 AC: 11988 AN: 41390

American (AMR) AF: 0.0435 AC: 664 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 28 AN: 3464

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4806

European-Finnish (FIN) AF: 0.00703 AC: 74 AN: 10526

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0175 AC: 1186 AN: 67942

Other (OTH) AF: 0.0715 AC: 151 AN: 2112

Alfa AF: 0.0372 Hom.: 1082

Bravo AF: 0.105

Asia WGS AF: 0.0330 AC: 116 AN: 3474

EpiCase AF: 0.0182

EpiControl AF: 0.0183

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	-0.69
CADD	Benign	8.9
DANN	Benign	0.72
PhyloP100		-0.40
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: rs6857760; hg19: chr4-103645082;