chr9-13224492-G-A

Position:

• chr9-13224492-G-A

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.275C>T​(p.Ser92Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00963 in 1,612,678 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. S92S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (99 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.73

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=0.0025561154).
• BP6: Variant 9-13224492-G-A is Benign according to our data. Variant chr9-13224492-G-A is described in ClinVar as [Benign]. Clinvar id is 774428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00813 (1237/152146) while in subpopulation NFE AF= 0.0118 (804/67974). AF 95% confidence interval is 0.0111. There are 11 homozygotes in gnomad4. There are 562 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPDZ	NM_001378778.1	c.275C>T	p.Ser92Leu	missense_variant	4/47	ENST00000319217.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPDZ	ENST00000319217.12	c.275C>T	p.Ser92Leu	missense_variant	4/47	5	NM_001378778.1	A1

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1237 AN: 152028 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00295

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00787

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00790 AC: 1961 AN: 248256 Hom.: 17 AF XY: 0.00853 AC XY: 1149 AN XY: 134694

Gnomad AFR exome AF: 0.00201

Gnomad AMR exome AF: 0.00655

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00624

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00997

GnomAD4 exome AF: 0.00979 AC: 14300 AN: 1460532 Hom.: 99 Cov.: 31 AF XY: 0.00973 AC XY: 7072 AN XY: 726580

Gnomad4 AFR exome AF: 0.00177

Gnomad4 AMR exome AF: 0.00707

Gnomad4 ASJ exome AF: 0.0261

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00622

Gnomad4 FIN exome AF: 0.000637

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.00897

GnomAD4 genome AF: 0.00813 AC: 1237 AN: 152146 Hom.: 11 Cov.: 32 AF XY: 0.00755 AC XY: 562 AN XY: 74402

Gnomad4 AFR AF: 0.00294

Gnomad4 AMR AF: 0.00786

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0101

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0120 Hom.: 26

Bravo AF: 0.00831

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0114 AC: 44

ESP6500AA AF: 0.00296 AC: 11

ESP6500EA AF: 0.0126 AC: 103

ExAC AF: 0.00824 AC: 995

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0142

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MPDZ: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T;.;.;.;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D;D;D;D;.;D
MetaRNN	Benign	0.0026	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;L;L;L;.
MutationTaster	Benign	0.65	N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D
REVEL	Benign	0.095
Sift	Benign	0.15	T;T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T;T
Polyphen		0.0090, 0.041	.;B;B;.;B;.
Vest4		0.085
MVP		0.23
ClinPred		0.024	T
GERP RS		3.0
Varity_R		0.062
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17273542; hg19: chr9-13224491;