rs16930134

Positions:

• chr9-13123296-T-C
• chr9-13123296-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378778.1(MPDZ):​c.4810A>G​(p.Thr1604Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 1,601,152 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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.

• Frequency:
  • Genomes: 𝑓 0.015 (55 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (56 hom.)
• Consequence: MPDZ NM_001378778.1 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.487

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=0.0017824173).
• BP6: Variant 9-13123296-T-C is Benign according to our data. Variant chr9-13123296-T-C is described in ClinVar as [Benign]. Clinvar id is 211517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPDZ	NM_001378778.1	c.4810A>G	p.Thr1604Ala	missense_variant, splice_region_variant	36/47	ENST00000319217.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPDZ	ENST00000319217.12	c.4810A>G	p.Thr1604Ala	missense_variant, splice_region_variant	36/47	5	NM_001378778.1	A1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2337 AN: 152094 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00391 AC: 885 AN: 226152 Hom.: 20 AF XY: 0.00291 AC XY: 355 AN XY: 122090

Gnomad AFR exome AF: 0.0577

Gnomad AMR exome AF: 0.00258

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: 0.0000992

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00148 AC: 2139 AN: 1448940 Hom.: 56 Cov.: 30 AF XY: 0.00121 AC XY: 873 AN XY: 719540

Gnomad4 AFR exome AF: 0.0527

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000832

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000624

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.0154 AC: 2338 AN: 152212 Hom.: 55 Cov.: 32 AF XY: 0.0143 AC XY: 1067 AN XY: 74428

Gnomad4 AFR AF: 0.0538

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00348 Hom.: 17

Bravo AF: 0.0173

ESP6500AA AF: 0.0513 AC: 190

ESP6500EA AF: 0.000488 AC: 4

ExAC AF: 0.00449 AC: 542

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 08, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.036	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T;T;T;D;T;T;T;.;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;.;.;.;.;.;.;.
MutationTaster	Benign	0.91	D;D;N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;N;.;N;N;N;N;N;N
REVEL	Benign	0.013
Sift	Benign	0.079	T;T;.;T;T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T;T;T;T;T
Polyphen		0.017	B;B;B;.;.;B;.;B;.
Vest4		0.091
MVP		0.31
ClinPred		0.0098	T
GERP RS		0.48
Varity_R		0.066
gMVP		0.32

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: rs16930134; hg19: chr9-13123295;