9-13190164-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378778.1(MPDZ):c.2104G>A(p.Glu702Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0134 in 1,612,982 control chromosomes in the GnomAD database, including 510 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E702V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.017 (51 hom., cov: 32)
  • Exomes 𝑓: 0.013 (459 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.59

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043197274).
• BP6: Variant 9-13190164-C-T is Benign according to our data. Variant chr9-13190164-C-T is described in ClinVar as [Benign]. Clinvar id is 211508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-13190164-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPDZ	NM_001378778.1	c.2104G>A	p.Glu702Lys	missense_variant	16/47	ENST00000319217.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPDZ	ENST00000319217.12	c.2104G>A	p.Glu702Lys	missense_variant	16/47	5	NM_001378778.1	A1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2612 AN: 152138 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.0804

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00815

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0189 AC: 4693 AN: 248078 Hom.: 138 AF XY: 0.0220 AC XY: 2958 AN XY: 134590

Gnomad AFR exome AF: 0.0319

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00287

Gnomad SAS exome AF: 0.0840

Gnomad FIN exome AF: 0.000558

Gnomad NFE exome AF: 0.00855

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0131 AC: 19079 AN: 1460726 Hom.: 459 Cov.: 30 AF XY: 0.0152 AC XY: 11016 AN XY: 726592

Gnomad4 AFR exome AF: 0.0338

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.00192

Gnomad4 SAS exome AF: 0.0799

Gnomad4 FIN exome AF: 0.000956

Gnomad4 NFE exome AF: 0.00808

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0171 AC: 2610 AN: 152256 Hom.: 51 Cov.: 32 AF XY: 0.0181 AC XY: 1344 AN XY: 74424

Gnomad4 AFR AF: 0.0329

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.00464

Gnomad4 SAS AF: 0.0805

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00815

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0105 Hom.: 27

Bravo AF: 0.0172

ExAC AF: 0.0207 AC: 2508

Asia WGS AF: 0.0470 AC: 165 AN: 3476

EpiCase AF: 0.0117

EpiControl AF: 0.0111

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 08, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2019

This variant is associated with the following publications: (PMID: 29924831) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.11	T;.;.;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;.;D
MetaRNN	Benign	0.0043	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;.
MutationTaster	Benign	0.92	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D
Polyphen		0.99, 0.94	.;D;P;.;P;.
Vest4		0.48
ClinPred		0.034	T
GERP RS		5.8
Varity_R		0.45
gMVP		0.60

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

Other links and lift over

dbSNP: rs4741289; hg19: chr9-13190163; COSMIC: COSV59945672;