rs188840960

chr9-13150559-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.46

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]

ACMG classification

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: {Benign=3, Uncertain_significance=2, Likely_benign=1}. 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPDZ	ENST00000319217.12	c.3582T>G	p.Ser1194Arg	missense_variant	25/47	5	NM_001378778.1	A1

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 712 AN: 152010 Hom.: 6 Cov.: 32

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.: 9 AF XY: 0.00457 AC XY: 583 AN XY: 127702

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.: 43 Cov.: 32 AF XY: 0.00643 AC XY: 4549 AN XY: 707212

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.: 6 Cov.: 32 AF XY: 0.00421 AC XY: 313 AN XY: 74380

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.: 10

Bravo AF: 0.00420

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00133 AC: 5

ESP6500EA AF: 0.00900 AC: 74

ExAC AF: 0.00525 AC: 634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

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) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MPDZ: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 31, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 09, 2019

- -

MPDZ-related condition Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.91	D
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	T
MutationAssessor	Pathogenic	3.2	M;M;M;.;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
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	T
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

Other links and lift over

dbSNP: rs188840960; hg19: chr9-13150558;