Genetic Variant MANBAL:p.Ala50Val (chr20-37301412-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001003897.2(MANBAL):c.149C>T(p.Ala50Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,610,476 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

MANBAL
NM_001003897.2 missense, splice_region

Scores

Splicing: ADA: 0.001224

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.398

Variant links:

Genes affected

MANBAL (HGNC:15799): (mannosidase beta like) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MANBAL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.006928891).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBAL	NM_001003897.2 link	c.149C>T	p.Ala50Val	missense_variant, splice_region_variant	Exon 2 of 3	ENST00000373606.8	NP_001003897.1	Q9NQG1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANBAL	ENST00000373606.8 link	c.149C>T	p.Ala50Val	missense_variant, splice_region_variant	Exon 2 of 3	1	NM_001003897.2	ENSP00000362708.3		Q9NQG1

Frequencies

GnomAD3 genomes

AF:

0.000644

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000184

AC:

AN:

249518

Hom.:

AF XY:

0.000156

AC XY:

AN XY:

134914

show subpopulations

Gnomad AFR exome

AF:

0.00180

Gnomad AMR exome

AF:

0.000235

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000549

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000619

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000857

AC:

125

AN:

1458206

Hom.:

Cov.:

AF XY:

0.0000744

AC XY:

AN XY:

725506

show subpopulations

Gnomad4 AFR exome

AF:

0.00147

Gnomad4 AMR exome

AF:

0.000472

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000644

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.0224

Hom.:

2354

Bravo

AF:

0.000752

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.149C>T (p.A50V) alteration is located in exon 3 (coding exon 1) of the MANBAL gene. This alteration results from a C to T substitution at nucleotide position 149, causing the alanine (A) at amino acid position 50 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.023

T;T;T;T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.50

.;T;.;.;T

M_CAP

Benign

0.0031

MetaRNN

Benign

0.0069

T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

0.010

N;N;N;N;N

REVEL

Benign

0.028

Sift

Benign

0.58

T;T;T;T;T

Sift4G

Benign

0.33

T;T;T;T;T

Polyphen

0.0

B;.;B;B;B

Vest4

0.074

MVP

0.076

MPC

0.13

ClinPred

0.0018

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.015

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.014

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over