Variant chr18-35101977-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_014268.4(MAPRE2):c.428G>A(p.Arg143His) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,558 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MAPRE2
NM_014268.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.95

Variant links:

Genes affected

MAPRE2 (HGNC:6891): (microtubule associated protein RP/EB family member 2) The protein encoded by this gene shares significant homology to the adenomatous polyposis coli (APC) protein-binding EB1 gene family. This protein is a microtubule-associated protein that is necessary for spindle symmetry during mitosis. It is thought to play a role in the tumorigenesis of colorectal cancers and the proliferative control of normal cells. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jan 2012]

MAPRE2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a domain Calponin-homology (CH) (size 102) in uniprot entity MARE2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_014268.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-35101976-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant where missense usually causes diseases, MAPRE2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPRE2	NM_014268.4 linkuse as main transcript	c.428G>A	p.Arg143His	missense_variant	4/7	ENST00000300249.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPRE2	ENST00000300249.10 linkuse as main transcript	c.428G>A	p.Arg143His	missense_variant	4/7	1	NM_014268.4	A1	Q15555-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457558

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725058

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.428G>A (p.R143H) alteration is located in exon 4 (coding exon 4) of the MAPRE2 gene. This alteration results from a G to A substitution at nucleotide position 428, causing the arginine (R) at amino acid position 143 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

D;.;T;.;D;D;.;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;.

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.69

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.50

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.92

Sift4G

Uncertain

0.0040

D;D;D;D;D;D;D;D;D

Polyphen

1.0, 0.99

.;.;.;.;.;D;.;D;.

Vest4

0.55, 0.61, 0.60, 0.54, 0.62, 0.59

MutPred

0.55

.;.;.;.;.;Loss of ubiquitination at K141 (P = 0.0429);.;Loss of ubiquitination at K141 (P = 0.0429);.;

MVP

0.65

MPC

3.2

ClinPred

0.99

GERP RS

5.3

Varity_R

0.55

gMVP

0.82

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over