9-13107063-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001378778.1(MPDZ):c.6115G>A(p.Ala2039Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000792 in 1,603,200 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 7.57

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046147555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPDZ	NM_001378778.1	c.6115G>A	p.Ala2039Thr	missense_variant	47/47	ENST00000319217.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPDZ	ENST00000319217.12	c.6115G>A	p.Ala2039Thr	missense_variant	47/47	5	NM_001378778.1	A1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000723 AC: 18 AN: 248938 Hom.: 0 AF XY: 0.0000815 AC XY: 11 AN XY: 135028

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000517 AC: 75 AN: 1450880 Hom.: 0 Cov.: 30 AF XY: 0.0000485 AC XY: 35 AN XY: 720942

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000352

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.000134

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74484

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0249 Hom.: 2351

Bravo AF: 0.000314

ESP6500AA AF: 0.00101 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 27, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2010 of the MPDZ protein (p.Ala2010Thr). This variant is present in population databases (rs140627050, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with MPDZ-related conditions. ClinVar contains an entry for this variant (Variation ID: 1177484). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Hydrocephalus, nonsyndromic, autosomal recessive 2 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 11-23-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.042	T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.046	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.3	N;N;.;D;D;D;N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0090	D;D;.;T;D;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;D;D;.;.;D;.;D;.
Vest4		0.76
MVP		0.49
ClinPred		0.23	T
GERP RS		5.5
Varity_R		0.44
gMVP		0.50

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: rs140627050; hg19: chr9-13107062;