9-13223593-G-C

Variant names:

• chr9-13223593-G-C
• rs181479224
• NM_001378778.1:c.511C>G

Variant summary

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

The ENST00000319217.12(MPDZ):​c.511C>G​(p.Gln171Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,612,108 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q171Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (6 hom.)
• Consequence: MPDZ ENST00000319217.12 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 9.60
• Publications: 8 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013445288).
• BP6: Variant 9-13223593-G-C is Benign according to our data. Variant chr9-13223593-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435884.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00172 (262/152162) while in subpopulation NFE AF = 0.00281 (191/67976). AF 95% confidence interval is 0.00248. There are 0 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000319217.12. 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.511C>G	p.Gln171Glu	missense	Exon 5 of 47	NP_001365707.1
	MPDZ	NM_001375413.1		c.511C>G	p.Gln171Glu	missense	Exon 5 of 48	NP_001362342.1
	MPDZ	NM_001330637.2		c.511C>G	p.Gln171Glu	missense	Exon 5 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.511C>G	p.Gln171Glu	missense	Exon 5 of 47	ENSP00000320006.7
	MPDZ	ENST00000541718.5	TSL:1	c.511C>G	p.Gln171Glu	missense	Exon 5 of 46	ENSP00000439807.1
	MPDZ	ENST00000447879.6	TSL:1	c.511C>G	p.Gln171Glu	missense	Exon 5 of 46	ENSP00000415208.1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00165 AC: 409 AN: 248362 AF XY: 0.00155

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.000613

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00288

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00265 AC: 3862 AN: 1459946 Hom.: 6 Cov.: 30 AF XY: 0.00255 AC XY: 1851 AN XY: 726268

African (AFR) AF: 0.000330 AC: 11 AN: 33356

American (AMR) AF: 0.000988 AC: 44 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00338 AC: 88 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86164

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00321 AC: 3568 AN: 1110776

Other (OTH) AF: 0.00222 AC: 134 AN: 60272

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74382

African (AFR) AF: 0.000530 AC: 22 AN: 41544

American (AMR) AF: 0.00197 AC: 30 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 67976

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00284 Hom.: 0

Bravo AF: 0.00202

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00134 AC: 5

ESP6500EA AF: 0.00304 AC: 25

ExAC AF: 0.00173 AC: 209

EpiCase AF: 0.00301

EpiControl AF: 0.00262

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.58
MVP		0.49
ClinPred		0.033	T
GERP RS		6.1
Varity_R		0.55
gMVP		0.29
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs181479224; hg19: chr9-13223592; COSMIC: COSV106453266; COSMIC: COSV106453266;