NM_001378778.1:c.275C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378778.1(MPDZ):c.275C>T(p.Ser92Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00963 in 1,612,678 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S92S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0081 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 99 hom. )

Consequence

MPDZ
NM_001378778.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.73

Publications

13 publications found

Variant links:

Genes affected

MPDZ (HGNC:7208): (multiple PDZ domain crumbs cell polarity complex component) The protein encoded by this gene has multiple PDZ domains, which are hallmarks of protein-protein interactions. The encoded protein is known to interact with the HTR2C receptor and may cause it to clump at the cell surface. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

MPDZ Gene-Disease associations (from GenCC):

hydrocephalus, nonsyndromic, autosomal recessive 2
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

MPDZ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025561154).

BP6

Variant 9-13224492-G-A is Benign according to our data. Variant chr9-13224492-G-A is described in ClinVar as Benign. ClinVar VariationId is 774428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00813 (1237/152146) while in subpopulation NFE AF = 0.0118 (804/67974). AF 95% confidence interval is 0.0111. There are 11 homozygotes in GnomAd4. There are 562 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPDZ	NM_001378778.1 link	c.275C>T	p.Ser92Leu	missense_variant	Exon 4 of 47	ENST00000319217.12	NP_001365707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPDZ	ENST00000319217.12 link	c.275C>T	p.Ser92Leu	missense_variant	Exon 4 of 47	5	NM_001378778.1	ENSP00000320006.7		O75970-1

Frequencies

GnomAD3 genomes

AF:

0.00814

AC:

1237

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00787

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00790

AC:

1961

AN:

248256

AF XY:

0.00853

show subpopulations

Gnomad AFR exome

AF:

0.00201

Gnomad AMR exome

AF:

0.00655

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000557

Gnomad NFE exome

AF:

0.0107

Gnomad OTH exome

AF:

0.00997

GnomAD4 exome

AF:

0.00979

AC:

14300

AN:

1460532

Hom.:

Cov.:

AF XY:

0.00973

AC XY:

7072

AN XY:

726580

show subpopulations

African (AFR)

AF:

0.00177

AC:

AN:

33410

American (AMR)

AF:

0.00707

AC:

315

AN:

44582

Ashkenazi Jewish (ASJ)

AF:

0.0261

AC:

681

AN:

26092

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39648

South Asian (SAS)

AF:

0.00622

AC:

536

AN:

86224

European-Finnish (FIN)

AF:

0.000637

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00781

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0109

AC:

12087

AN:

1111128

Other (OTH)

AF:

0.00897

AC:

541

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

672

1345

2017

2690

3362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.00813

AC:

1237

AN:

152146

Hom.:

Cov.:

AF XY:

0.00755

AC XY:

562

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00294

AC:

122

AN:

41532

American (AMR)

AF:

0.00786

AC:

120

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5148

South Asian (SAS)

AF:

0.0101

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0118

AC:

804

AN:

67974

Other (OTH)

AF:

0.0118

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0113

Hom.:

Bravo

AF:

0.00831

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00296

AC:

ESP6500EA

AF:

0.0126

AC:

103

ExAC

AF:

0.00824

AC:

995

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0113

EpiControl

AF:

0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MPDZ: BP4, BS1, BS2 -

not specified

Benign:1

Mar 13, 2020

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.087

T;.;.;.;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.87

D;D;D;D;.;D

MetaRNN

Benign

0.0026

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;L;L;L;.

PhyloP100

3.7

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.6

D;D;D;D;D;D

REVEL

Benign

0.095

Sift

Benign

0.15

T;T;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T;T

Polyphen

0.0090, 0.041

.;B;B;.;B;.

Vest4

0.085

MVP

0.23

ClinPred

0.024

GERP RS

3.0

Varity_R

0.062

gMVP

0.38

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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