Variant 1-37794445-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000373045.11(MANEAL):c.263C>A(p.Pro88His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,523,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

MANEAL
ENST00000373045.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.40

Variant links:

Genes affected

MANEAL (HGNC:26452): (mannosidase endo-alpha like) Predicted to enable alpha-mannosidase activity. Predicted to be located in Golgi membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

MANEAL 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=0.035590827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANEAL	NM_001113482.2 linkuse as main transcript	c.263C>A	p.Pro88His	missense_variant	1/4	ENST00000373045.11	NP_001106954.1	Q5VSG8-1
MANEAL	NM_001031740.3 linkuse as main transcript	c.263C>A	p.Pro88His	missense_variant	1/4		NP_001026910.1	Q5VSG8-3
MANEAL	XM_005270510.4 linkuse as main transcript	c.263C>A	p.Pro88His	missense_variant	1/3		XP_005270567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MANEAL	ENST00000373045.11 linkuse as main transcript	c.263C>A	p.Pro88His	missense_variant	1/4	1	NM_001113482.2	ENSP00000362136.6	Q5VSG8-1
MANEAL	ENST00000397631.7 linkuse as main transcript	c.263C>A	p.Pro88His	missense_variant	1/4	1		ENSP00000380755.3	Q5VSG8-3
MANEAL	ENST00000532512.1 linkuse as main transcript	c.-38C>A		upstream_gene_variant		4		ENSP00000432567.1	H0YCZ3

Frequencies

GnomAD3 genomes

AF:

0.000286

AC:

AN:

150164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00139

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:

0.000148

Gnomad OTH

AF:

0.00146

GnomAD3 exomes

AF:

0.000398

AC:

AN:

133184

Hom.:

AF XY:

0.000356

AC XY:

AN XY:

72936

show subpopulations

Gnomad AFR exome

AF:

0.000176

Gnomad AMR exome

AF:

0.00123

Gnomad ASJ exome

AF:

0.000127

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000478

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000274

AC:

376

AN:

1373208

Hom.:

Cov.:

AF XY:

0.000258

AC XY:

175

AN XY:

677250

show subpopulations

Gnomad4 AFR exome

AF:

0.000194

Gnomad4 AMR exome

AF:

0.00135

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:

0.000268

Gnomad4 OTH exome

AF:

0.000532

GnomAD4 genome

AF:

0.000286

AC:

AN:

150280

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

AN XY:

73382

show subpopulations

Gnomad4 AFR

AF:

0.000219

Gnomad4 AMR

AF:

0.00139

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000148

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.000188

Hom.:

Bravo

AF:

0.000484

ExAC

AF:

0.000153

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2021

The c.263C>A (p.P88H) alteration is located in exon 1 (coding exon 1) of the MANEAL gene. This alteration results from a C to A substitution at nucleotide position 263, causing the proline (P) at amino acid position 88 to be replaced by a histidine (H). 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

0.12

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-0.091

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.42

T;T

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.97

N;N

REVEL

Benign

0.12

Sift

Benign

0.052

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.92

P;D

Vest4

0.27

MutPred

0.12

Loss of glycosylation at P88 (P = 0.013);Loss of glycosylation at P88 (P = 0.013);

MVP

0.20

MPC

1.3

ClinPred

0.035

GERP RS

3.3

Varity_R

0.099

gMVP

0.38

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

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