rs149169783

Positions:

• chr9-13190278-A-G

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.1990T>C​(p.Phe664Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,602,294 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0064 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (7 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.330

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=0.0049014986).
• BP6: Variant 9-13190278-A-G is Benign according to our data. Variant chr9-13190278-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 445626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00636 (967/152128) while in subpopulation AFR AF= 0.0224 (928/41508). AF 95% confidence interval is 0.0212. There are 14 homozygotes in gnomad4. There are 438 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPDZ	NM_001378778.1	c.1990T>C	p.Phe664Leu	missense_variant	16/47	ENST00000319217.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPDZ	ENST00000319217.12	c.1990T>C	p.Phe664Leu	missense_variant	16/47	5	NM_001378778.1	A1

Frequencies

GnomAD3 genomes AF: 0.00637 AC: 968 AN: 152010 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

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: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00161 AC: 388 AN: 240322 Hom.: 2 AF XY: 0.00117 AC XY: 153 AN XY: 130392

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.000571

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: 0.0000364

Gnomad OTH exome AF: 0.000518

GnomAD4 exome AF: 0.000669 AC: 970 AN: 1450166 Hom.: 7 Cov.: 30 AF XY: 0.000587 AC XY: 423 AN XY: 720636

Gnomad4 AFR exome AF: 0.0255

Gnomad4 AMR exome AF: 0.000845

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000903

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00636 AC: 967 AN: 152128 Hom.: 14 Cov.: 32 AF XY: 0.00589 AC XY: 438 AN XY: 74354

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00284 Hom.: 2

Bravo AF: 0.00695

ESP6500AA AF: 0.0198 AC: 80

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00194 AC: 234

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -

MPDZ-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 11, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.026	T;.;.;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.73	T;T;T;T;.;T
MetaRNN	Benign	0.0049	T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.83	L;L;L;L;L;.
MutationTaster	Benign	0.97	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.80	T;T;T;T;T;T
Sift4G	Benign	0.39	T;T;T;T;T;T
Polyphen		0.0010, 0.0	.;B;B;.;B;.
Vest4		0.15
MutPred		0.33		Gain of disorder (P = 0.0845);Gain of disorder (P = 0.0845);Gain of disorder (P = 0.0845);Gain of disorder (P = 0.0845);Gain of disorder (P = 0.0845);Gain of disorder (P = 0.0845);
MVP		0.17
ClinPred		0.0060	T
GERP RS		1.9
Varity_R		0.069
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs149169783; hg19: chr9-13190277;