rs188840960

Positions:

chr9-13150559-A-C

Variant summary

Our verdict is Benign. Variant got -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

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:

MPDZ (HGNC:):

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=0.013053536).

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 id is 376860.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=2}. Variant chr9-13150559-A-C is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPDZ	NM_001378778.1 linkuse as main transcript	c.3582T>G	p.Ser1194Arg	missense_variant	25/47	ENST00000319217.12	NP_001365707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPDZ	ENST00000319217.12 linkuse as main transcript	c.3582T>G	p.Ser1194Arg	missense_variant	25/47	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

GnomAD3 exomes

AF:

0.00459

AC:

1073

AN:

233936

Hom.:

AF XY:

0.00457

AC XY:

583

AN XY:

127702

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 SAS exome

AF:

0.000480

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

Gnomad4 AFR exome

AF:

0.00104

Gnomad4 AMR exome

AF:

0.000948

Gnomad4 ASJ exome

AF:

0.00127

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000481

Gnomad4 FIN exome

AF:

0.00872

Gnomad4 NFE exome

AF:

0.00775

Gnomad4 OTH exome

AF:

0.00469

GnomAD4 genome

AF:

0.00468

AC:

712

AN:

152128

Hom.:

Cov.:

AF XY:

0.00421

AC XY:

313

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.000985

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00725

Gnomad4 NFE

AF:

0.00758

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00643

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MPDZ: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	Identified at a greater frequency in control alleles than in alleles from a cohort of individuals with keratoconus (Lucas et al., 2018); 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) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 09, 2019

- -

MPDZ-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2019

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

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;.;.;.

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

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

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