rs864309720

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP2PP5_Very_Strong

The ENST00000300249.10(MAPRE2):​c.427C>T​(p.Arg143Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R143H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

MAPRE2
ENST00000300249.10 missense

Scores

6
9
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.16
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 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 ENST00000300249.10
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAPRE2. . Gene score misZ 3.1867 (greater than the threshold 3.09). Trascript score misZ 4.3282 (greater than threshold 3.09). GenCC has associacion of gene with multiple benign circumferential skin creases on limbs 1, skin creases, congenital symmetric circumferential, 2, multiple benign circumferential skin creases on limbs.
PP5
Variant 18-35101976-C-T is Pathogenic according to our data. 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. Variant chr18-35101976-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MAPRE2NM_014268.4 linkuse as main transcriptc.427C>T p.Arg143Cys missense_variant 4/7 ENST00000300249.10 NP_055083.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MAPRE2ENST00000300249.10 linkuse as main transcriptc.427C>T p.Arg143Cys missense_variant 4/71 NM_014268.4 ENSP00000300249 A1Q15555-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
0.00
AC:
0
AN:
1456792
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
724640
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Skin creases, congenital symmetric circumferential, 2 Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 03, 2015- -
Likely pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MAPRE2-related disorder (ClinVar ID: VCV000218930 / PMID: 26637975). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26637975). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Developmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingDepartment of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized MedicineSep 26, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.;T;.;D;D;.;.;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;.
M_CAP
Benign
0.038
D
MetaRNN
Uncertain
0.68
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.50
T
MutationAssessor
Uncertain
2.8
.;.;.;.;.;M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-6.4
.;D;.;D;.;D;D;.;.
REVEL
Uncertain
0.35
Sift
Benign
0.043
.;D;.;D;.;T;D;.;.
Sift4G
Uncertain
0.031
D;D;D;T;D;T;D;T;D
Polyphen
0.15, 0.093
.;.;.;.;.;B;.;B;.
Vest4
0.75, 0.81, 0.80, 0.77, 0.81, 0.85
MutPred
0.62
.;.;.;.;.;Loss of MoRF binding (P = 0.065);.;Loss of MoRF binding (P = 0.065);.;
MVP
0.78
MPC
2.2
ClinPred
0.98
D
GERP RS
5.3
Varity_R
0.78
gMVP
0.90

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.

Other links and lift over

dbSNP: rs864309720; hg19: chr18-32681940; API