rs188840960

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378778.1(MPDZ):c.3582T>G(p.Ser1194Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00637 in 1,575,090 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0047 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0066 ( 43 hom. )

Consequence

MPDZ
NM_001378778.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 1.46

Publications

17 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013053536).

BP6

Variant 9-13150559-A-C is Benign according to our data. Variant chr9-13150559-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376860.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00468 (712/152128) while in subpopulation NFE AF = 0.00758 (515/67978). AF 95% confidence interval is 0.00703. There are 6 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPDZ	NM_001378778.1 link	c.3582T>G	p.Ser1194Arg	missense_variant	Exon 25 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.3582T>G	p.Ser1194Arg	missense_variant	Exon 25 of 47	5	NM_001378778.1	ENSP00000320006.7		O75970-1

Frequencies

GnomAD3 genomes

AF:

0.00468

AC:

712

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.000986

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00725

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00758

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00459

AC:

1073

AN:

233936

AF XY:

0.00457

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.000891

Gnomad ASJ exome

AF:

0.00133

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00796

Gnomad NFE exome

AF:

0.00747

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00655

AC:

9326

AN:

1422962

Hom.:

Cov.:

AF XY:

0.00643

AC XY:

4549

AN XY:

707212

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

31772

American (AMR)

AF:

0.000948

AC:

AN:

42202

Ashkenazi Jewish (ASJ)

AF:

0.00127

AC:

AN:

25290

East Asian (EAS)

AF:

0.00

AC:

AN:

37666

South Asian (SAS)

AF:

0.000481

AC:

AN:

79076

European-Finnish (FIN)

AF:

0.00872

AC:

452

AN:

51816

Middle Eastern (MID)

AF:

0.000534

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

0.00775

AC:

8454

AN:

1091082

Other (OTH)

AF:

0.00469

AC:

274

AN:

58438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

Heterozygous variant carriers

474

947

1421

1894

2368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

338

676

1014

1352

1690

<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:

0.00468

AC:

712

AN:

152128

Hom.:

Cov.:

AF XY:

0.00421

AC XY:

313

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41536

American (AMR)

AF:

0.000985

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.000866

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00725

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00758

AC:

515

AN:

67978

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00601

Hom.:

Bravo

AF:

0.00420

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00133

AC:

ESP6500EA

AF:

0.00900

AC:

ExAC

AF:

0.00525

AC:

634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MPDZ: BS2 -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 14, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified at a greater frequency in control alleles than in alleles from a cohort of individuals with keratoconus (PMID: 29924831); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29924831) -

Jan 31, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 09, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

MPDZ-related disorder

Benign:1

Jul 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

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

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

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

MetaRNN

Benign

0.013

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Pathogenic

3.2

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

PhyloP100

1.5

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.7

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

REVEL

Uncertain

0.54

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.93

MutPred

0.83

.;.;.;.;Loss of ubiquitination at K90 (P = 0.0533);.;.;.;Loss of ubiquitination at K90 (P = 0.0533);Loss of ubiquitination at K90 (P = 0.0533);

MVP

0.43

ClinPred

0.070

GERP RS

2.5

Varity_R

0.79

gMVP

0.88

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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