rs745854560

Variant names:

• chr9-13107075-C-A
• rs745854560
• NM_001378778.1:c.6103G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-13107075-C-A
• chr9-13107075-C-T
• chr9-13107075-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001378778.1(MPDZ):​c.6103G>T​(p.Asp2035Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,434,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2035N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 4 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: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

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.6103G>T	p.Asp2035Tyr	missense	Exon 47 of 47	NP_001365707.1	O75970-1
	MPDZ	NM_001375413.1		c.6202G>T	p.Asp2068Tyr	missense	Exon 48 of 48	NP_001362342.1
	MPDZ	NM_001330637.2		c.6103G>T	p.Asp2035Tyr	missense	Exon 47 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.6103G>T	p.Asp2035Tyr	missense	Exon 47 of 47	ENSP00000320006.7	O75970-1
	MPDZ	ENST00000541718.5	TSL:1	c.6016G>T	p.Asp2006Tyr	missense	Exon 46 of 46	ENSP00000439807.1	O75970-2
	MPDZ	ENST00000447879.6	TSL:1	c.6004G>T	p.Asp2002Tyr	missense	Exon 46 of 46	ENSP00000415208.1	O75970-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000322 AC: 8 AN: 248234 AF XY: 0.0000594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 21 AN: 1434754 Hom.: 0 Cov.: 30 AF XY: 0.0000267 AC XY: 19 AN XY: 710486

African (AFR) AF: 0.0000301 AC: 1 AN: 33178

American (AMR) AF: 0.00 AC: 0 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25566

East Asian (EAS) AF: 0.00 AC: 0 AN: 39204

South Asian (SAS) AF: 0.000227 AC: 19 AN: 83708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091482

Other (OTH) AF: 0.0000170 AC: 1 AN: 58952

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hydrocephalus, nonsyndromic, autosomal recessive 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.91		Loss of ubiquitination at K2032 (P = 0.0417)
MVP		0.93
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.87
Mutation Taster		=20/80	disease causing

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: rs745854560; hg19: chr9-13107074;