9-13107002-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378778.1(MPDZ):c.6176G>A(p.Arg2059Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00086 in 1,613,532 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2059W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (3 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.69

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009553522).
• BP6: Variant 9-13107002-C-T is Benign according to our data. Variant chr9-13107002-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 791296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-13107002-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0047 (715/152234) while in subpopulation AFR AF= 0.0162 (673/41538). AF 95% confidence interval is 0.0152. There are 5 homozygotes in gnomad4. There are 340 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPDZ	NM_001378778.1	c.6176G>A	p.Arg2059Gln	missense_variant	47/47	ENST00000319217.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPDZ	ENST00000319217.12	c.6176G>A	p.Arg2059Gln	missense_variant	47/47	5	NM_001378778.1	A1

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 717 AN: 152116 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00671

GnomAD3 exomes AF: 0.00123 AC: 307 AN: 249260 Hom.: 1 AF XY: 0.000895 AC XY: 121 AN XY: 135222

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000460 AC: 672 AN: 1461298 Hom.: 3 Cov.: 30 AF XY: 0.000391 AC XY: 284 AN XY: 726970

Gnomad4 AFR exome AF: 0.0166

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00470 AC: 715 AN: 152234 Hom.: 5 Cov.: 32 AF XY: 0.00457 AC XY: 340 AN XY: 74430

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.000858 Hom.: 2

Bravo AF: 0.00513

ESP6500AA AF: 0.0165 AC: 66

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00151 AC: 182

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MPDZ-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 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

Jan 06, 2024

- -

Hydrocephalus, nonsyndromic, autosomal recessive 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.039	T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;.;D
MetaRNN	Benign	0.0096	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.1	N;N;.;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.21	T;T;.;T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T
Polyphen		0.95	P;D;D;.;.;P;.;D;.
Vest4		0.28
MVP		0.36
ClinPred		0.030	T
GERP RS		4.6
Varity_R		0.33
gMVP		0.23

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: rs193280665; hg19: chr9-13107001;