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.2914C>T(p.Pro972Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,599,220 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P972A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 2 hom. )

Consequence

MPDZ
NM_001378778.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.351

Publications

2 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=0.0029535592).

BP6

Variant 9-13176153-G-A is Benign according to our data. Variant chr9-13176153-G-A is described in ClinVar as Benign. ClinVar VariationId is 211512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000361 (55/152268) while in subpopulation EAS AF = 0.0102 (53/5174). AF 95% confidence interval is 0.00804. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378778.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MPDZ	NM_001378778.1	MANE Select	c.2914C>T	p.Pro972Ser	missense	Exon 20 of 47	NP_001365707.1
MPDZ	NM_001375413.1		c.2914C>T	p.Pro972Ser	missense	Exon 20 of 48	NP_001362342.1
MPDZ	NM_001330637.2		c.2914C>T	p.Pro972Ser	missense	Exon 20 of 47	NP_001317566.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MPDZ	ENST00000319217.12	TSL:5 MANE Select	c.2914C>T	p.Pro972Ser	missense	Exon 20 of 47	ENSP00000320006.7
MPDZ	ENST00000541718.5	TSL:1	c.2914C>T	p.Pro972Ser	missense	Exon 20 of 46	ENSP00000439807.1
MPDZ	ENST00000447879.6	TSL:1	c.2914C>T	p.Pro972Ser	missense	Exon 20 of 46	ENSP00000415208.1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0102

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00107

AC:

245

AN:

228328

AF XY:

0.00109

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0145

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000355

GnomAD4 exome

AF:

0.000296

AC:

429

AN:

1446952

Hom.:

Cov.:

AF XY:

0.000299

AC XY:

215

AN XY:

718080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33266

American (AMR)

AF:

0.00

AC:

AN:

42936

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25678

East Asian (EAS)

AF:

0.00977

AC:

383

AN:

39212

South Asian (SAS)

AF:

0.0000358

AC:

AN:

83860

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52674

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103744

Other (OTH)

AF:

0.000702

AC:

AN:

59852

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000361

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41552

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0102

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000448

Hom.:

Bravo

AF:

0.000397

ExAC

AF:

0.000912

AC:

110

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

MPDZ-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.053

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

PhyloP100

0.35

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.6

REVEL

Benign

0.061

Sift

Benign

0.12

Sift4G

Benign

0.42

Polyphen

0.0010

Vest4

0.042

MVP

0.10

ClinPred

0.017

GERP RS

4.0

PromoterAI

-0.0079

Neutral

(source)

Varity_R

0.025

gMVP

0.26

Mutation Taster

=100/0

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

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

rs186662317

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over