rs186662317

chr9-13176153-G-Achr9-13176153-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001378778.1(MPDZ):c.2914C>T(p.Pro972Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,599,220 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P972P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (2 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.351

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029535592).
• BP6: Variant 9-13176153-G-A is Benign according to our data. Variant chr9-13176153-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000361 (55/152268) while in subpopulation EAS AF= 0.0102 (53/5174). AF 95% confidence interval is 0.00804. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPDZ	NM_001378778.1	c.2914C>T	p.Pro972Ser	missense_variant	20/47	ENST00000319217.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPDZ	ENST00000319217.12	c.2914C>T	p.Pro972Ser	missense_variant	20/47	5	NM_001378778.1	A1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152150 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00107 AC: 245 AN: 228328 Hom.: 1 AF XY: 0.00109 AC XY: 134 AN XY: 123086

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0145

Gnomad SAS exome AF: 0.0000357

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000355

GnomAD4 exome AF: 0.000296 AC: 429 AN: 1446952 Hom.: 2 Cov.: 31 AF XY: 0.000299 AC XY: 215 AN XY: 718080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00977

Gnomad4 SAS exome AF: 0.0000358

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.000702

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152268 Hom.: 0 Cov.: 33 AF XY: 0.000390 AC XY: 29 AN XY: 74448

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0102

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.000397

ExAC AF: 0.000912 AC: 110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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

Feb 17, 2017

- -

MPDZ-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	10
Dann	Benign	0.86
DEOGEN2	Benign	0.053	T;.;.;.;.;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.67	T;T;T;T;.;T
MetaRNN	Benign	0.0030	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.12	T;T;T;T;T;T
Sift4G	Benign	0.42	T;T;T;T;T;T
Polyphen		0.0010	.;B;B;.;B;.
Vest4		0.042
MVP		0.10
ClinPred		0.017	T
GERP RS		4.0
Varity_R		0.025
gMVP		0.26

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: rs186662317; hg19: chr9-13176152;