rs188840960

Variant names:

• chr9-13150559-A-C
• rs188840960
• NM_001378778.1:c.3582T>G
• MPDZ p.Ser1194Arg

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378778.1(MPDZ):​c.3582T>G​(p.Ser1194Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00637 in 1,575,090 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0047 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (43 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.46
• Publications: 17 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013053536).
• BP6: Variant 9-13150559-A-C is Benign according to our data. Variant chr9-13150559-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376860.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00468 (712/152128) while in subpopulation NFE AF = 0.00758 (515/67978). AF 95% confidence interval is 0.00703. There are 6 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378778.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	NM_001378778.1	MANE Select	c.3582T>G	p.Ser1194Arg	missense	Exon 25 of 47	NP_001365707.1	O75970-1
	MPDZ	NM_001375413.1		c.3582T>G	p.Ser1194Arg	missense	Exon 25 of 48	NP_001362342.1
	MPDZ	NM_001330637.2		c.3582T>G	p.Ser1194Arg	missense	Exon 25 of 47	NP_001317566.1	O75970-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	ENST00000319217.12	TSL:5 MANE Select	c.3582T>G	p.Ser1194Arg	missense	Exon 25 of 47	ENSP00000320006.7	O75970-1
	MPDZ	ENST00000541718.5	TSL:1	c.3582T>G	p.Ser1194Arg	missense	Exon 25 of 46	ENSP00000439807.1	O75970-2
	MPDZ	ENST00000447879.6	TSL:1	c.3582T>G	p.Ser1194Arg	missense	Exon 25 of 46	ENSP00000415208.1	O75970-3

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 712 AN: 152010 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.000986

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00758

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00459 AC: 1073 AN: 233936 AF XY: 0.00457

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.000891

Gnomad ASJ exome AF: 0.00133

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00796

Gnomad NFE exome AF: 0.00747

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00655 AC: 9326 AN: 1422962 Hom.: 43 Cov.: 32 AF XY: 0.00643 AC XY: 4549 AN XY: 707212

African (AFR) AF: 0.00104 AC: 33 AN: 31772

American (AMR) AF: 0.000948 AC: 40 AN: 42202

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 32 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 37666

South Asian (SAS) AF: 0.000481 AC: 38 AN: 79076

European-Finnish (FIN) AF: 0.00872 AC: 452 AN: 51816

Middle Eastern (MID) AF: 0.000534 AC: 3 AN: 5620

European-Non Finnish (NFE) AF: 0.00775 AC: 8454 AN: 1091082

Other (OTH) AF: 0.00469 AC: 274 AN: 58438

GnomAD4 genome AF: 0.00468 AC: 712 AN: 152128 Hom.: 6 Cov.: 32 AF XY: 0.00421 AC XY: 313 AN XY: 74380

African (AFR) AF: 0.00142 AC: 59 AN: 41536

American (AMR) AF: 0.000985 AC: 15 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00758 AC: 515 AN: 67978

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00601 Hom.: 18

Bravo AF: 0.00420

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	1	MPDZ-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.79
gMVP		0.88
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs188840960;

hg19: chr9-13150558;