Genetic Variant MPDZ:c.5380-16C>G (chr9-13115350-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001378778.1(MPDZ):c.5380-16C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,595,530 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0095 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 23 hom. )

Consequence

MPDZ
NM_001378778.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.537

Publications

1 publications found

Variant links:

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]

MPDZ Gene-Disease associations (from GenCC):

hydrocephalus, nonsyndromic, autosomal recessive 2
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

MPDZ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00947 (1441/152174) while in subpopulation AFR AF = 0.0249 (1035/41522). AF 95% confidence interval is 0.0237. There are 8 homozygotes in GnomAd4. There are 671 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPDZ	NM_001378778.1 link	c.5380-16C>G		intron_variant	Intron 39 of 46	ENST00000319217.12	NP_001365707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPDZ	ENST00000319217.12 link	c.5380-16C>G		intron_variant	Intron 39 of 46	5	NM_001378778.1	ENSP00000320006.7		O75970-1

Frequencies

GnomAD3 genomes

AF:

0.00944

AC:

1436

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00432

Gnomad OTH

AF:

0.00865

GnomAD2 exomes

AF:

0.00440

AC:

1054

AN:

239562

AF XY:

0.00404

show subpopulations

Gnomad AFR exome

AF:

0.0267

Gnomad AMR exome

AF:

0.00349

Gnomad ASJ exome

AF:

0.00112

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000513

Gnomad NFE exome

AF:

0.00454

Gnomad OTH exome

AF:

0.00304

GnomAD4 exome

AF:

0.00467

AC:

6745

AN:

1443356

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

3203

AN XY:

719144

show subpopulations

African (AFR)

AF:

0.0277

AC:

919

AN:

33132

American (AMR)

AF:

0.00384

AC:

171

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.000923

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39608

South Asian (SAS)

AF:

0.00150

AC:

129

AN:

85870

European-Finnish (FIN)

AF:

0.000632

AC:

AN:

52242

Middle Eastern (MID)

AF:

0.00836

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00468

AC:

5126

AN:

1096426

Other (OTH)

AF:

0.00494

AC:

295

AN:

59774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

347

694

1041

1388

1735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00947

AC:

1441

AN:

152174

Hom.:

Cov.:

AF XY:

0.00902

AC XY:

671

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0249

AC:

1035

AN:

41522

American (AMR)

AF:

0.00517

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00104

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00432

AC:

294

AN:

68008

Other (OTH)

AF:

0.00856

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

153

230

306

383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.0104

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.41

(source)

DANN

Benign

0.51

PhyloP100

-0.54

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over