Genetic Variant MPP7:p.Lys322Thr (chr10-28089829-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001318170.2(MPP7):c.965A>C(p.Lys322Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000735 in 1,361,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K322Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

MPP7
NM_001318170.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.86

Publications

0 publications found

Variant links:

Genes affected

MPP7 (HGNC:26542): (MAGUK p55 scaffold protein 7) The protein encoded by this gene is a member of the p55 Stardust family of membrane-associated guanylate kinase (MAGUK) proteins, which function in the establishment of epithelial cell polarity. This family member forms a complex with the polarity protein DLG1 (discs, large homolog 1) and facilitates epithelial cell polarity and tight junction formation. Polymorphisms in this gene are associated with variations in site-specific bone mineral density (BMD). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

MPP7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25628358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPP7	NM_001318170.2 link	c.965A>C	p.Lys322Thr	missense_variant	Exon 12 of 17	ENST00000683449.1	NP_001305099.1	Q5T2T1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPP7	ENST00000683449.1 link	c.965A>C	p.Lys322Thr	missense_variant	Exon 12 of 17		NM_001318170.2	ENSP00000507917.1		Q5T2T1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.35e-7

AC:

AN:

1361308

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

680384

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31106

American (AMR)

AF:

0.0000241

AC:

AN:

41560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24740

East Asian (EAS)

AF:

0.00

AC:

AN:

38970

South Asian (SAS)

AF:

0.00

AC:

AN:

77026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5478

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1033702

Other (OTH)

AF:

0.00

AC:

AN:

56694

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.056

T;T;T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.090

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.88

D;.;.;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.0

N;N;N;.

PhyloP100

5.9

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.018

D;D;D;D

Sift4G

Uncertain

0.029

D;D;D;D

Polyphen

0.010

B;B;B;.

Vest4

0.30

MutPred

0.26

Loss of methylation at K322 (P = 0.0121);Loss of methylation at K322 (P = 0.0121);Loss of methylation at K322 (P = 0.0121);.;

MVP

0.89

MPC

0.21

ClinPred

0.85

GERP RS

5.8

Varity_R

0.21

gMVP

0.45

Mutation Taster

=55/45

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over