rs41265286

Positions:

• chr9-13158063-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001378778.1(MPDZ):​c.3407G>A​(p.Ser1136Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,612,790 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (9 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.70

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006310791).
• BP6: Variant 9-13158063-C-T is Benign according to our data. Variant chr9-13158063-C-T is described in ClinVar as [Benign]. Clinvar id is 740408.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00201 (2934/1460552) while in subpopulation NFE AF= 0.002 (2219/1111182). AF 95% confidence interval is 0.00193. There are 9 homozygotes in gnomad4_exome. There are 1397 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPDZ	NM_001378778.1	c.3407G>A	p.Ser1136Asn	missense_variant	24/47	ENST00000319217.12	NP_001365707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPDZ	ENST00000319217.12	c.3407G>A	p.Ser1136Asn	missense_variant	24/47	5	NM_001378778.1	ENSP00000320006	A1

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152120 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00223 AC: 554 AN: 248442 Hom.: 5 AF XY: 0.00221 AC XY: 298 AN XY: 134836

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.00231

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00201 AC: 2934 AN: 1460552 Hom.: 9 Cov.: 30 AF XY: 0.00192 AC XY: 1397 AN XY: 726532

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.00200

Gnomad4 OTH exome AF: 0.00216

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152238 Hom.: 1 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74408

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.00184

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00159 Hom.: 0

Bravo AF: 0.00114

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00106 AC: 4

ESP6500EA AF: 0.00182 AC: 15

ExAC AF: 0.00229 AC: 276

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

MPDZ-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2023

This variant is classified as 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;.;.;.;.;.;.;.;.;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;.;D;D;D
MetaRNN	Benign	0.0063	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.3	M;M;M;.;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D;D;D;T;T;D;D;T;T;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;.;.
Polyphen		1.0, 0.99	.;D;D;.;D;.;D;.;.;.
Vest4		0.54
MVP		0.50
ClinPred		0.035	T
GERP RS		5.9
Varity_R		0.30
gMVP		0.47

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: rs41265286; hg19: chr9-13158062; COSMIC: COSV105182814;