9-13223593-G-C

Position:

• chr9-13223593-G-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.511C>G​(p.Gln171Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,612,108 control chromosomes in the GnomAD database, including 6 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 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (6 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 9.60

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=0.013445288).
• BP6: Variant 9-13223593-G-C is Benign according to our data. Variant chr9-13223593-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435884.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr9-13223593-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00172 (262/152162) while in subpopulation NFE AF= 0.00281 (191/67976). AF 95% confidence interval is 0.00248. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPDZ	NM_001378778.1	c.511C>G	p.Gln171Glu	missense_variant	5/47	ENST00000319217.12	NP_001365707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPDZ	ENST00000319217.12	c.511C>G	p.Gln171Glu	missense_variant	5/47	5	NM_001378778.1	ENSP00000320006	A1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00165 AC: 409 AN: 248362 Hom.: 2 AF XY: 0.00155 AC XY: 209 AN XY: 134736

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.000613

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00288

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00265 AC: 3862 AN: 1459946 Hom.: 6 Cov.: 30 AF XY: 0.00255 AC XY: 1851 AN XY: 726268

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.000988

Gnomad4 ASJ exome AF: 0.00338

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00321

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74382

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00197

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00284 Hom.: 0

Bravo AF: 0.00202

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00134 AC: 5

ESP6500EA AF: 0.00304 AC: 25

ExAC AF: 0.00173 AC: 209

EpiCase AF: 0.00301

EpiControl AF: 0.00262

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MPDZ: BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 20, 2016

- -

MPDZ-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T;.;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;.;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.028	D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		0.99	.;D;D;.;D;.
Vest4		0.58
MVP		0.49
ClinPred		0.033	T
GERP RS		6.1
Varity_R		0.55
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs181479224; hg19: chr9-13223592;