X-154779227-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002436.4(MPP1):​c.1351G>A​(p.Asp451Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000281 in 1,210,111 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.000027 ( 0 hom. 13 hem. )

Consequence

MPP1
NM_002436.4 missense

Scores

2
4
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.86
Variant links:
Genes affected
MPP1 (HGNC:7219): (MAGUK p55 scaffold protein 1) This gene encodes the prototype of the membrane-associated guanylate kinase (MAGUK) family proteins. MAGUKs interact with the cytoskeleton and regulate cell proliferation, signaling pathways, and intercellular junctions. The encoded protein is an extensively palmitoylated membrane phosphoprotein containing a PDZ domain, a Src homology 3 (SH3) motif, and a guanylate kinase domain. This gene product interacts with various cytoskeletal proteins and cell junctional proteins in different tissue and cell types, and may be involved in the regulation of cell shape, hair cell development, neural patterning of the retina, and apico-basal polarity and tumor suppression pathways in non-erythroid cells. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.21582794).
BS2
High Hemizygotes in GnomAdExome4 at 13 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MPP1NM_002436.4 linkc.1351G>A p.Asp451Asn missense_variant Exon 12 of 12 ENST00000369534.8 NP_002427.1 Q00013-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MPP1ENST00000369534.8 linkc.1351G>A p.Asp451Asn missense_variant Exon 12 of 12 1 NM_002436.4 ENSP00000358547.3 Q00013-1

Frequencies

GnomAD3 genomes
AF:
0.0000357
AC:
4
AN:
112057
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34221
show subpopulations
Gnomad AFR
AF:
0.0000649
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00427
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000273
AC:
5
AN:
183174
Hom.:
0
AF XY:
0.0000444
AC XY:
3
AN XY:
67610
show subpopulations
Gnomad AFR exome
AF:
0.000152
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000105
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000221
GnomAD4 exome
AF:
0.0000273
AC:
30
AN:
1098000
Hom.:
0
Cov.:
30
AF XY:
0.0000358
AC XY:
13
AN XY:
363368
show subpopulations
Gnomad4 AFR exome
AF:
0.000114
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000333
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000107
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000357
AC:
4
AN:
112111
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34285
show subpopulations
Gnomad4 AFR
AF:
0.0000648
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1351G>A (p.D451N) alteration is located in exon 12 (coding exon 12) of the MPP1 gene. This alteration results from a G to A substitution at nucleotide position 1351, causing the aspartic acid (D) at amino acid position 451 to be replaced by an asparagine (N). 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
0.073
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.75
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;.;.
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.83
T;T;T
M_CAP
Pathogenic
0.34
D
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;.;.
PrimateAI
Benign
0.36
T
PROVEAN
Uncertain
-2.8
D;D;D
REVEL
Benign
0.11
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.055
T;T;D
Polyphen
0.71
P;.;.
Vest4
0.045
MutPred
0.41
Gain of sheet (P = 0.0827);.;.;
MVP
0.57
MPC
0.55
ClinPred
0.27
T
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.50
gMVP
0.40

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: rs782511750; hg19: chrX-154007502; API