NM_001378778.1:c.2104G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378778.1(MPDZ):c.2104G>A(p.Glu702Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0134 in 1,612,982 control chromosomes in the GnomAD database, including 510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E702V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.017 ( 51 hom., cov: 32)

Exomes 𝑓: 0.013 ( 459 hom. )

Consequence

MPDZ
NM_001378778.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.59

Publications

10 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=0.0043197274).

BP6

Variant 9-13190164-C-T is Benign according to our data. Variant chr9-13190164-C-T is described in ClinVar as Benign. ClinVar VariationId is 211508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPDZ	NM_001378778.1 link	c.2104G>A	p.Glu702Lys	missense_variant	Exon 16 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.2104G>A	p.Glu702Lys	missense_variant	Exon 16 of 47	5	NM_001378778.1	ENSP00000320006.7		O75970-1

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2612

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0330

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.0132

Gnomad EAS

AF:

0.00482

Gnomad SAS

AF:

0.0804

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00815

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.0189

AC:

4693

AN:

248078

AF XY:

0.0220

show subpopulations

Gnomad AFR exome

AF:

0.0319

Gnomad AMR exome

AF:

0.0113

Gnomad ASJ exome

AF:

0.0119

Gnomad EAS exome

AF:

0.00287

Gnomad FIN exome

AF:

0.000558

Gnomad NFE exome

AF:

0.00855

Gnomad OTH exome

AF:

0.0178

GnomAD4 exome

AF:

0.0131

AC:

19079

AN:

1460726

Hom.:

459

Cov.:

AF XY:

0.0152

AC XY:

11016

AN XY:

726592

show subpopulations

African (AFR)

AF:

0.0338

AC:

1131

AN:

33436

American (AMR)

AF:

0.0114

AC:

507

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

276

AN:

26112

East Asian (EAS)

AF:

0.00192

AC:

AN:

39560

South Asian (SAS)

AF:

0.0799

AC:

6872

AN:

86060

European-Finnish (FIN)

AF:

0.000956

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.0295

AC:

170

AN:

5760

European-Non Finnish (NFE)

AF:

0.00808

AC:

8977

AN:

1111470

Other (OTH)

AF:

0.0169

AC:

1019

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

898

1795

2693

3590

4488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

436

872

1308

1744

2180

<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:

0.0171

AC:

2610

AN:

152256

Hom.:

Cov.:

AF XY:

0.0181

AC XY:

1344

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0329

AC:

1366

AN:

41562

American (AMR)

AF:

0.0116

AC:

177

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0132

AC:

AN:

3472

East Asian (EAS)

AF:

0.00464

AC:

AN:

5174

South Asian (SAS)

AF:

0.0805

AC:

388

AN:

4822

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00815

AC:

554

AN:

68008

Other (OTH)

AF:

0.0222

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

119

239

358

478

597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0114

Hom.:

Bravo

AF:

0.0172

ExAC

AF:

0.0207

AC:

2508

Asia WGS

AF:

0.0470

AC:

165

AN:

3476

EpiCase

AF:

0.0117

EpiControl

AF:

0.0111

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Apr 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29924831) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Apr 08, 2013

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

0.17

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

T;.;.;.;.;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D;.;D

MetaRNN

Benign

0.0043

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;M;M;M;M;.

PhyloP100

4.6

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D

REVEL

Benign

0.17

Sift

Uncertain

0.0040

D;D;D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D;D;D

Polyphen

0.99, 0.94

.;D;P;.;P;.

Vest4

0.48

ClinPred

0.034

GERP RS

5.8

Varity_R

0.45

gMVP

0.60

Mutation Taster

=95/5

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over