chr9-13119603-C-T

Variant names:

• chr9-13119603-C-T
• rs1554644827
• NM_001378778.1:c.5278G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001378778.1(MPDZ):​c.5278G>A​(p.Ala1760Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:2
• Conservation: PhyloP100: 7.88
• Publications: 1 publications found

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]

MPDZ Gene-Disease associations (from GenCC):

• hydrocephalus, nonsyndromic, autosomal recessive 2

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378778.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	NM_001378778.1	MANE Select	c.5278G>A	p.Ala1760Thr	missense	Exon 39 of 47	NP_001365707.1
	MPDZ	NM_001375413.1		c.5377G>A	p.Ala1793Thr	missense	Exon 40 of 48	NP_001362342.1
	MPDZ	NM_001330637.2		c.5278G>A	p.Ala1760Thr	missense	Exon 39 of 47	NP_001317566.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	ENST00000319217.12	TSL:5 MANE Select	c.5278G>A	p.Ala1760Thr	missense	Exon 39 of 47	ENSP00000320006.7
	MPDZ	ENST00000541718.5	TSL:1	c.5278G>A	p.Ala1760Thr	missense	Exon 39 of 46	ENSP00000439807.1
	MPDZ	ENST00000447879.6	TSL:1	c.5179G>A	p.Ala1727Thr	missense	Exon 38 of 46	ENSP00000415208.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727108

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111832

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hydrocephalus, nonsyndromic, autosomal recessive 2 Pathogenic:1 Uncertain:1

Jul 10, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jan 29, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Uncertain:1

Dec 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine with threonine at codon 1760 of the MPDZ protein (p.Ala1760Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hydrocephalus (PMID: 28556411). ClinVar contains an entry for this variant (Variation ID: 548150). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.89		Gain of methylation at K1756 (P = 0.1002)
MVP		0.90
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.66
gMVP		0.52
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554644827; hg19: chr9-13119602;