rs745508809

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_033066.3(MPP4):c.1379C>T(p.Pro460Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000206 in 1,598,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

MPP4
NM_033066.3 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.91

Publications

0 publications found

Variant links:

Genes affected

MPP4 (HGNC:13680): (MAGUK p55 scaffold protein 4) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) protein family, with an N-terminal PDZ domain, a central src homology 3 region (SH3), and a C-terminal guanylate kinase-like (GUK) domain. The protein is localized to the outer limiting membrane in the retina, and is thought to function in photoreceptor polarity and the organization of specialized intercellular junctions. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

MPP4 links:

ENSG00000287133 (HGNC:):

ENSG00000287133 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.45414 (below the threshold of 3.09). Trascript score misZ: 0.68092 (below the threshold of 3.09).

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPP4	NM_033066.3 link	c.1379C>T	p.Pro460Leu	missense_variant, splice_region_variant	Exon 18 of 22	ENST00000409474.8	NP_149055.2	Q96JB8-1
MPP4	NM_001438024.1 link	c.1286C>T	p.Pro429Leu	missense_variant, splice_region_variant	Exon 14 of 18		NP_001424953.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPP4	ENST00000409474.8 link	c.1379C>T	p.Pro460Leu	missense_variant, splice_region_variant	Exon 18 of 22	1	NM_033066.3	ENSP00000387278.3		Q96JB8-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000132

AC:

AN:

227634

AF XY:

0.0000163

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000293

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000180

AC:

AN:

1446088

Hom.:

Cov.:

AF XY:

0.0000237

AC XY:

AN XY:

717686

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33220

American (AMR)

AF:

0.00

AC:

AN:

42504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25792

East Asian (EAS)

AF:

0.00

AC:

AN:

39312

South Asian (SAS)

AF:

0.00

AC:

AN:

82926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52754

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1103906

Other (OTH)

AF:

0.000100

AC:

AN:

59918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 24, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1379C>T (p.P460L) alteration is located in exon 18 (coding exon 17) of the MPP4 gene. This alteration results from a C to T substitution at nucleotide position 1379, causing the proline (P) at amino acid position 460 to be replaced by a leucine (L). 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

0.76

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;T;T;.;T;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.87

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

MetaSVM

Uncertain

-0.19

MutationAssessor

Pathogenic

3.5

M;.;.;.;.;.;.;.

PhyloP100

6.9

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.6

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

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.99

MVP

0.89

MPC

0.38

ClinPred

0.99

GERP RS

5.5

Varity_R

0.92

gMVP

0.82

Mutation Taster

=11/89

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over