rs34605667

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378778.1(MPDZ):​c.5723G>A​(p.Arg1908Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0386 in 1,613,092 control chromosomes in the GnomAD database, including 1,421 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 111 hom., cov: 33)
Exomes 𝑓: 0.039 ( 1310 hom. )

Consequence

MPDZ
NM_001378778.1 missense, splice_region

Scores

2
16
Splicing: ADA: 0.002675
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.62
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005102515).
BP6
Variant 9-13112025-C-T is Benign according to our data. Variant chr9-13112025-C-T is described in ClinVar as [Benign]. Clinvar id is 211519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-13112025-C-T is described in Lovd as [Benign]. Variant chr9-13112025-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0306 (4665/152256) while in subpopulation NFE AF= 0.0445 (3027/68020). AF 95% confidence interval is 0.0432. There are 111 homozygotes in gnomad4. There are 2353 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 111 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MPDZNM_001378778.1 linkuse as main transcriptc.5723G>A p.Arg1908Lys missense_variant, splice_region_variant 43/47 ENST00000319217.12 NP_001365707.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MPDZENST00000319217.12 linkuse as main transcriptc.5723G>A p.Arg1908Lys missense_variant, splice_region_variant 43/475 NM_001378778.1 ENSP00000320006.7 O75970-1

Frequencies

GnomAD3 genomes
AF:
0.0307
AC:
4666
AN:
152138
Hom.:
111
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00830
Gnomad AMI
AF:
0.0208
Gnomad AMR
AF:
0.0176
Gnomad ASJ
AF:
0.0300
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.0122
Gnomad FIN
AF:
0.0743
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.0445
Gnomad OTH
AF:
0.0244
GnomAD3 exomes
AF:
0.0328
AC:
8174
AN:
249038
Hom.:
167
AF XY:
0.0335
AC XY:
4527
AN XY:
135092
show subpopulations
Gnomad AFR exome
AF:
0.00646
Gnomad AMR exome
AF:
0.0153
Gnomad ASJ exome
AF:
0.0319
Gnomad EAS exome
AF:
0.0000557
Gnomad SAS exome
AF:
0.0140
Gnomad FIN exome
AF:
0.0727
Gnomad NFE exome
AF:
0.0442
Gnomad OTH exome
AF:
0.0402
GnomAD4 exome
AF:
0.0394
AC:
57521
AN:
1460836
Hom.:
1310
Cov.:
31
AF XY:
0.0388
AC XY:
28231
AN XY:
726700
show subpopulations
Gnomad4 AFR exome
AF:
0.00535
Gnomad4 AMR exome
AF:
0.0170
Gnomad4 ASJ exome
AF:
0.0325
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0152
Gnomad4 FIN exome
AF:
0.0720
Gnomad4 NFE exome
AF:
0.0435
Gnomad4 OTH exome
AF:
0.0352
GnomAD4 genome
AF:
0.0306
AC:
4665
AN:
152256
Hom.:
111
Cov.:
33
AF XY:
0.0316
AC XY:
2353
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.00828
Gnomad4 AMR
AF:
0.0176
Gnomad4 ASJ
AF:
0.0300
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.0120
Gnomad4 FIN
AF:
0.0743
Gnomad4 NFE
AF:
0.0445
Gnomad4 OTH
AF:
0.0241
Alfa
AF:
0.0388
Hom.:
207
Bravo
AF:
0.0262
TwinsUK
AF:
0.0437
AC:
162
ALSPAC
AF:
0.0462
AC:
178
ESP6500AA
AF:
0.00784
AC:
30
ESP6500EA
AF:
0.0402
AC:
332
ExAC
AF:
0.0331
AC:
3994
Asia WGS
AF:
0.00693
AC:
24
AN:
3478
EpiCase
AF:
0.0406
EpiControl
AF:
0.0419

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 08, 2013- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.61
CADD
Uncertain
24
DANN
Benign
0.72
DEOGEN2
Benign
0.014
T;.;.;.;.;.;.;.;.
Eigen
Benign
-0.21
Eigen_PC
Benign
0.026
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.72
T;T;T;T;T;T;T;.;T
MetaRNN
Benign
0.0051
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-1.0
N;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.010
N;N;.;N;N;N;N;N;N
REVEL
Benign
0.20
Sift
Benign
0.66
T;T;.;T;T;T;T;T;T
Sift4G
Benign
0.95
T;T;T;T;T;T;T;T;T
Polyphen
0.033
B;P;B;.;.;B;.;B;.
Vest4
0.24
ClinPred
0.025
T
GERP RS
5.7
Varity_R
0.16
gMVP
0.28

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0027
dbscSNV1_RF
Benign
0.096
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.

Other links and lift over

dbSNP: rs34605667; hg19: chr9-13112024; API