9-13140097-G-C

Variant names:

• chr9-13140097-G-C
• rs76115127
• NM_001378778.1:c.3893C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378778.1(MPDZ):​c.3893C>G​(p.Pro1298Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1298L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• Publications: 0 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25173467).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	NM_001378778.1	MANE Select	c.3893C>G	p.Pro1298Arg	missense	Exon 28 of 47	NP_001365707.1
	MPDZ	NM_001375413.1		c.3893C>G	p.Pro1298Arg	missense	Exon 28 of 48	NP_001362342.1
	MPDZ	NM_001330637.2		c.3893C>G	p.Pro1298Arg	missense	Exon 28 of 47	NP_001317566.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	ENST00000319217.12	TSL:5 MANE Select	c.3893C>G	p.Pro1298Arg	missense	Exon 28 of 47	ENSP00000320006.7
	MPDZ	ENST00000541718.5	TSL:1	c.3893C>G	p.Pro1298Arg	missense	Exon 28 of 46	ENSP00000439807.1
	MPDZ	ENST00000447879.6	TSL:1	c.3794C>G	p.Pro1265Arg	missense	Exon 27 of 46	ENSP00000415208.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.0035
Eigen_PC	Benign	-0.018
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.9
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.040
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.038	D
Polyphen		0.91	P
Vest4		0.46
MutPred		0.34		Loss of glycosylation at P157 (P = 0.0125)
MVP		0.38
ClinPred		0.66	D
GERP RS		3.0
Varity_R		0.096
gMVP		0.54
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs76115127; hg19: chr9-13140096;