Genetic Variant NM_001378778.1:c.2155-25A>G (chr9-13189018-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001378778.1(MPDZ):c.2155-25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,593,518 control chromosomes in the GnomAD database, including 244 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. There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.013 ( 27 hom., cov: 32)

Exomes 𝑓: 0.015 ( 217 hom. )

Consequence

MPDZ
NM_001378778.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.213

Publications

3 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 -8 ACMG points.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0127 (1925/152138) while in subpopulation AMR AF = 0.0173 (264/15264). AF 95% confidence interval is 0.0163. There are 27 homozygotes in GnomAd4. There are 927 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPDZ	NM_001378778.1 link	c.2155-25A>G		intron_variant	Intron 16 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.2155-25A>G		intron_variant	Intron 16 of 46	5	NM_001378778.1	ENSP00000320006.7

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1927

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00341

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0173

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0171

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0137

AC:

3257

AN:

237858

AF XY:

0.0140

show subpopulations

Gnomad AFR exome

AF:

0.00239

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.0441

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0147

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.0184

GnomAD4 exome

AF:

0.0154

AC:

22197

AN:

1441380

Hom.:

217

Cov.:

AF XY:

0.0154

AC XY:

11046

AN XY:

715788

show subpopulations

African (AFR)

AF:

0.00310

AC:

102

AN:

32914

American (AMR)

AF:

0.0122

AC:

530

AN:

43538

Ashkenazi Jewish (ASJ)

AF:

0.0439

AC:

1126

AN:

25634

East Asian (EAS)

AF:

0.00

AC:

AN:

39278

South Asian (SAS)

AF:

0.00450

AC:

380

AN:

84512

European-Finnish (FIN)

AF:

0.0125

AC:

657

AN:

52490

Middle Eastern (MID)

AF:

0.0319

AC:

181

AN:

5674

European-Non Finnish (NFE)

AF:

0.0166

AC:

18185

AN:

1097882

Other (OTH)

AF:

0.0174

AC:

1036

AN:

59458

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1110

2220

3330

4440

5550

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

670

1340

2010

2680

3350

<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:

0.0127

AC:

1925

AN:

152138

Hom.:

Cov.:

AF XY:

0.0125

AC XY:

927

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00340

AC:

141

AN:

41528

American (AMR)

AF:

0.0173

AC:

264

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0418

AC:

145

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00249

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0136

AC:

144

AN:

10590

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0171

AC:

1166

AN:

67996

Other (OTH)

AF:

0.0180

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

103

206

308

411

514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0160

Hom.:

Bravo

AF:

0.0129

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

0.21

La Branchor

0.84

BranchPoint Hunter

6.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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