chr9-13219604-C-G

Variant summary

Our verdict is Benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L347L) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.0030 ( 2 hom., cov: 32)
Exomes š‘“: 0.0042 ( 19 hom. )

Consequence

MPDZ
NM_001378778.1 missense

Scores

3
16

Clinical Significance

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

Conservation

PhyloP100: 0.854

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

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=0.00850448).
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 submission is: [Conflicting_classifications_of_pathogenicity].
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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MPDZNM_001378778.1 linkc.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
MPDZENST00000319217.12 linkc.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.:
2
Cov.:
32
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
GnomAD2 exomes
AF:
0.00285
AC:
708
AN:
248226
AF XY:
0.00296
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 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.:
19
Cov.:
32
AF XY:
0.00407
AC XY:
2957
AN XY:
726444
show subpopulations
African (AFR)
AF:
0.000868
AC:
29
AN:
33396
American (AMR)
AF:
0.00400
AC:
178
AN:
44544
Ashkenazi Jewish (ASJ)
AF:
0.00188
AC:
49
AN:
26068
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39626
South Asian (SAS)
AF:
0.000464
AC:
40
AN:
86224
European-Finnish (FIN)
AF:
0.000338
AC:
18
AN:
53294
Middle Eastern (MID)
AF:
0.00208
AC:
12
AN:
5756
European-Non Finnish (NFE)
AF:
0.00502
AC:
5574
AN:
1111116
Other (OTH)
AF:
0.00317
AC:
191
AN:
60262
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.477
Heterozygous variant carriers
0
341
683
1024
1366
1707
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
220
440
660
880
1100
<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:
0.00297
AC:
451
AN:
151976
Hom.:
2
Cov.:
32
AF XY:
0.00287
AC XY:
213
AN XY:
74258
show subpopulations
African (AFR)
AF:
0.00116
AC:
48
AN:
41532
American (AMR)
AF:
0.00289
AC:
44
AN:
15200
Ashkenazi Jewish (ASJ)
AF:
0.00173
AC:
6
AN:
3462
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5128
South Asian (SAS)
AF:
0.000624
AC:
3
AN:
4806
European-Finnish (FIN)
AF:
0.000188
AC:
2
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00492
AC:
334
AN:
67914
Other (OTH)
AF:
0.00663
AC:
14
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
25
51
76
102
127
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
10
20
30
40
50
<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:
0.00439
Hom.:
0
Bravo
AF:
0.00320
TwinsUK
AF:
0.00593
AC:
22
ALSPAC
AF:
0.00311
AC:
12
ESP6500AA
AF:
0.000496
AC:
2
ESP6500EA
AF:
0.00359
AC:
30
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
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Mar 20, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

MPDZ: BP4, BS2 -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hydrocephalus, nonsyndromic, autosomal recessive 2 Uncertain:1
Apr 02, 2018
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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

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
0.069
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.083
T;.;.;.;.;.
Eigen
Benign
-0.026
Eigen_PC
Benign
0.031
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.78
T;T;T;T;.;T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.0085
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N;N;N;N;.
PhyloP100
0.85
PrimateAI
Benign
0.27
T
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
T
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.070
gMVP
0.11
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs34911705; hg19: chr9-13219603; API