chr9-13219604-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378778.1(MPDZ):c.1041G>C(p.Leu347Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,612,262 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 19 hom. )

Consequence

MPDZ
NM_001378778.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.854

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00850448).

BP6

Variant 9-13219604-C-G is Benign according to our data. Variant chr9-13219604-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211506.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=3}. Variant chr9-13219604-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00297 (451/151976) while in subpopulation NFE AF= 0.00492 (334/67914). AF 95% confidence interval is 0.00448. There are 2 homozygotes in gnomad4. There are 213 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPDZ	NM_001378778.1 link	c.1041G>C	p.Leu347Phe	missense_variant	Exon 8 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.1041G>C	p.Leu347Phe	missense_variant	Exon 8 of 47	5	NM_001378778.1	ENSP00000320006.7		O75970-1

Frequencies

GnomAD3 genomes

AF:

0.00297

AC:

451

AN:

151858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00290

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00492

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00285

AC:

708

AN:

248226

Hom.:

AF XY:

0.00296

AC XY:

399

AN XY:

134716

show subpopulations

Gnomad AFR exome

AF:

0.000907

Gnomad AMR exome

AF:

0.00347

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00466

Gnomad OTH exome

AF:

0.00450

GnomAD4 exome

AF:

0.00417

AC:

6091

AN:

1460286

Hom.:

Cov.:

AF XY:

0.00407

AC XY:

2957

AN XY:

726444

show subpopulations

Gnomad4 AFR exome

AF:

0.000868

Gnomad4 AMR exome

AF:

0.00400

Gnomad4 ASJ exome

AF:

0.00188

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000464

Gnomad4 FIN exome

AF:

0.000338

Gnomad4 NFE exome

AF:

0.00502

Gnomad4 OTH exome

AF:

0.00317

GnomAD4 genome

AF:

0.00297

AC:

451

AN:

151976

Hom.:

Cov.:

AF XY:

0.00287

AC XY:

213

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00116

Gnomad4 AMR

AF:

0.00289

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00492

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00439

Hom.:

Bravo

AF:

0.00320

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000496

AC:

ESP6500EA

AF:

0.00359

AC:

ExAC

AF:

0.00296

AC:

358

EpiCase

AF:

0.00360

EpiControl

AF:

0.00541

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MPDZ: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2025	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hydrocephalus, nonsyndromic, autosomal recessive 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 02, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

T;.;.;.;.;.

Eigen

Benign

-0.026

Eigen_PC

Benign

0.031

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

T;T;T;T;.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0085

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;N;N;N;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

N;N;N;N;N;N

REVEL

Benign

0.059

Sift

Uncertain

0.025

D;T;T;D;D;T

Sift4G

Benign

0.19

T;T;T;T;T;T

Polyphen

0.93

.;P;P;.;P;.

Vest4

0.18

MutPred

0.26

Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);Loss of disorder (P = 0.1335);

MVP

0.27

ClinPred

0.020

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.070

gMVP

0.11

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over