rs34605667

Variant names:

• chr9-13112025-C-T
• rs34605667
• NM_001378778.1:c.5723G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378778.1(MPDZ):​c.5723G>A​(p.Arg1908Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0386 in 1,613,092 control chromosomes in the GnomAD database, including 1,421 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (111 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1310 hom.)
• Consequence: MPDZ NM_001378778.1 missense, splice_region
• Scores: Splicing: ADA: 0.002675
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.62
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005102515).
• BP6: Variant 9-13112025-C-T is Benign according to our data. Variant chr9-13112025-C-T is described in ClinVar as Benign. ClinVar VariationId is 211519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0306 (4665/152256) while in subpopulation NFE AF = 0.0445 (3027/68020). AF 95% confidence interval is 0.0432. There are 111 homozygotes in GnomAd4. There are 2353 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 111 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	NM_001378778.1	MANE Select	c.5723G>A	p.Arg1908Lys	missense splice_region	Exon 43 of 47	NP_001365707.1
	MPDZ	NM_001375413.1		c.5822G>A	p.Arg1941Lys	missense splice_region	Exon 44 of 48	NP_001362342.1
	MPDZ	NM_001330637.2		c.5723G>A	p.Arg1908Lys	missense splice_region	Exon 43 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.5723G>A	p.Arg1908Lys	missense splice_region	Exon 43 of 47	ENSP00000320006.7
	MPDZ	ENST00000541718.5	TSL:1	c.5636G>A	p.Arg1879Lys	missense splice_region	Exon 42 of 46	ENSP00000439807.1
	MPDZ	ENST00000447879.6	TSL:1	c.5624G>A	p.Arg1875Lys	missense splice_region	Exon 42 of 46	ENSP00000415208.1

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4666 AN: 152138 Hom.: 111 Cov.: 33

Gnomad AFR AF: 0.00830

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0445

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0328 AC: 8174 AN: 249038 AF XY: 0.0335

Gnomad AFR exome AF: 0.00646

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.0319

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0727

Gnomad NFE exome AF: 0.0442

Gnomad OTH exome AF: 0.0402

GnomAD4 exome AF: 0.0394 AC: 57521 AN: 1460836 Hom.: 1310 Cov.: 31 AF XY: 0.0388 AC XY: 28231 AN XY: 726700

African (AFR) AF: 0.00535 AC: 179 AN: 33452

American (AMR) AF: 0.0170 AC: 759 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 849 AN: 26106

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39670

South Asian (SAS) AF: 0.0152 AC: 1307 AN: 86182

European-Finnish (FIN) AF: 0.0720 AC: 3839 AN: 53354

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5766

European-Non Finnish (NFE) AF: 0.0435 AC: 48296 AN: 1111284

Other (OTH) AF: 0.0352 AC: 2121 AN: 60326

GnomAD4 genome AF: 0.0306 AC: 4665 AN: 152256 Hom.: 111 Cov.: 33 AF XY: 0.0316 AC XY: 2353 AN XY: 74446

African (AFR) AF: 0.00828 AC: 344 AN: 41554

American (AMR) AF: 0.0176 AC: 269 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4828

European-Finnish (FIN) AF: 0.0743 AC: 787 AN: 10594

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0445 AC: 3027 AN: 68020

Other (OTH) AF: 0.0241 AC: 51 AN: 2116

Alfa AF: 0.0369 Hom.: 288

Bravo AF: 0.0262

TwinsUK AF: 0.0437 AC: 162

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.00784 AC: 30

ESP6500EA AF: 0.0402 AC: 332

ExAC AF: 0.0331 AC: 3994

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0406

EpiControl AF: 0.0419

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.61
CADD	Uncertain	24
DANN	Benign	0.72
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	N
PhyloP100		4.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.20
Sift	Benign	0.66	T
Sift4G	Benign	0.95	T
Polyphen		0.033	B
Vest4		0.24
ClinPred		0.025	T
GERP RS		5.7
Varity_R		0.16
gMVP		0.28
Mutation Taster		=63/37	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0027
dbscSNV1_RF	Benign	0.096
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: rs34605667; hg19: chr9-13112024; COSMIC: COSV107397712;