rs34704118

Positions:

• chr9-13183487-T-C
• chr9-13183487-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001378778.1(MPDZ):​c.2580A>G​(p.Leu860=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00582 in 1,612,418 control chromosomes in the GnomAD database, including 39 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 0.0040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (39 hom.)
• Consequence: MPDZ NM_001378778.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.108

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-13183487-T-C is Benign according to our data. Variant chr9-13183487-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211510.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.108 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00404 (614/152084) while in subpopulation NFE AF= 0.00629 (427/67928). AF 95% confidence interval is 0.00579. There are 0 homozygotes in gnomad4. There are 284 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPDZ	NM_001378778.1	c.2580A>G	p.Leu860=	synonymous_variant	19/47	ENST00000319217.12	NP_001365707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPDZ	ENST00000319217.12	c.2580A>G	p.Leu860=	synonymous_variant	19/47	5	NM_001378778.1	ENSP00000320006	A1

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00467

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00629

Gnomad OTH AF: 0.00671

GnomAD3 exomes AF: 0.00440 AC: 1089 AN: 247636 Hom.: 2 AF XY: 0.00451 AC XY: 606 AN XY: 134346

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00918

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00334

Gnomad FIN exome AF: 0.000559

Gnomad NFE exome AF: 0.00644

Gnomad OTH exome AF: 0.00634

GnomAD4 exome AF: 0.00600 AC: 8767 AN: 1460334 Hom.: 39 Cov.: 31 AF XY: 0.00594 AC XY: 4318 AN XY: 726430

Gnomad4 AFR exome AF: 0.000928

Gnomad4 AMR exome AF: 0.00350

Gnomad4 ASJ exome AF: 0.00851

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00354

Gnomad4 FIN exome AF: 0.000769

Gnomad4 NFE exome AF: 0.00680

Gnomad4 OTH exome AF: 0.00650

GnomAD4 genome AF: 0.00404 AC: 614 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.00382 AC XY: 284 AN XY: 74348

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00466

Gnomad4 ASJ AF: 0.00894

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00629

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00470 Hom.: 1

Bravo AF: 0.00487

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.00873

EpiControl AF: 0.00667

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MPDZ: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 29, 2014

- -

MPDZ-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 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
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.2
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34704118; hg19: chr9-13183486;