chr4-102690688-C-T

Variant names:

• chr4-102690688-C-T
• rs227368
• NM_005908.4:c.757G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000647097.2(MANBA):​c.757G>A​(p.Val253Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 1,608,542 control chromosomes in the GnomAD database, including 177,288 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V253V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.40 (13451 hom., cov: 30)
  • Exomes 𝑓: 0.47 (163837 hom.)
• Consequence: MANBA ENST00000647097.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.114
• Publications: 55 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2812018E-4).
• BP6: Variant 4-102690688-C-T is Benign according to our data. Variant chr4-102690688-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 347096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000647097.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	NM_005908.4	MANE Select	c.757G>A	p.Val253Ile	missense	Exon 6 of 17	NP_005899.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MANBA	ENST00000647097.2	MANE Select	c.757G>A	p.Val253Ile	missense	Exon 6 of 17	ENSP00000495247.1
	MANBA	ENST00000642252.1		c.757G>A	p.Val253Ile	missense	Exon 6 of 18	ENSP00000495483.1
	MANBA	ENST00000644159.1		c.757G>A	p.Val253Ile	missense	Exon 6 of 18	ENSP00000494462.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60244 AN: 151564 Hom.: 13440 Cov.: 30

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.387

GnomAD2 exomes AF: 0.442 AC: 110738 AN: 250716 AF XY: 0.453

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.473

Gnomad EAS exome AF: 0.440

Gnomad FIN exome AF: 0.552

Gnomad NFE exome AF: 0.484

Gnomad OTH exome AF: 0.444

GnomAD4 exome AF: 0.469 AC: 683469 AN: 1456860 Hom.: 163837 Cov.: 33 AF XY: 0.471 AC XY: 341743 AN XY: 724962

African (AFR) AF: 0.183 AC: 6091 AN: 33342

American (AMR) AF: 0.302 AC: 13460 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 12295 AN: 26030

East Asian (EAS) AF: 0.503 AC: 19882 AN: 39530

South Asian (SAS) AF: 0.492 AC: 42295 AN: 85946

European-Finnish (FIN) AF: 0.556 AC: 29641 AN: 53300

Middle Eastern (MID) AF: 0.402 AC: 2311 AN: 5742

European-Non Finnish (NFE) AF: 0.479 AC: 530592 AN: 1108206

Other (OTH) AF: 0.447 AC: 26902 AN: 60144

GnomAD4 genome AF: 0.397 AC: 60267 AN: 151682 Hom.: 13451 Cov.: 30 AF XY: 0.399 AC XY: 29595 AN XY: 74092

African (AFR) AF: 0.193 AC: 7989 AN: 41396

American (AMR) AF: 0.358 AC: 5441 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1576 AN: 3472

East Asian (EAS) AF: 0.462 AC: 2383 AN: 5156

South Asian (SAS) AF: 0.502 AC: 2416 AN: 4814

European-Finnish (FIN) AF: 0.566 AC: 5900 AN: 10420

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33237 AN: 67904

Other (OTH) AF: 0.394 AC: 829 AN: 2104

Alfa AF: 0.459 Hom.: 74486

Bravo AF: 0.371

TwinsUK AF: 0.494 AC: 1830

ALSPAC AF: 0.477 AC: 1837

ESP6500AA AF: 0.211 AC: 929

ESP6500EA AF: 0.475 AC: 4081

ExAC AF: 0.442 AC: 53716

Asia WGS AF: 0.443 AC: 1541 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Beta-D-mannosidosis (3)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.4
DANN	Benign	0.79
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.00013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.11
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.032
Sift	Benign	0.45	T
Sift4G	Benign	0.39	T
Polyphen		0.016	B
Vest4		0.069
MPC		0.063
ClinPred		0.00087	T
GERP RS		1.3
Varity_R		0.012
gMVP		0.22
Mutation Taster		=99/1	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: rs227368; hg19: chr4-103611845; COSMIC: COSV56963409;