rs34704118

Variant names:

• chr9-13183487-T-C
• rs34704118
• NM_001378778.1:c.2580A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-13183487-T-C
• chr9-13183487-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001375413.1(MPDZ):​c.2580A>G​(p.Leu860Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00582 in 1,612,418 control chromosomes in the GnomAD database, including 39 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 0.0040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (39 hom.)
• Consequence: MPDZ NM_001375413.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.108
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-13183487-T-C is Benign according to our data. Variant chr9-13183487-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211510.
• BP7: Synonymous conserved (PhyloP=-0.108 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00404 (614/152084) while in subpopulation NFE AF = 0.00629 (427/67928). AF 95% confidence interval is 0.00579. There are 0 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 39 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375413.1. 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.2580A>G	p.Leu860Leu	synonymous	Exon 19 of 47	NP_001365707.1
	MPDZ	NM_001375413.1		c.2580A>G	p.Leu860Leu	synonymous	Exon 19 of 48	NP_001362342.1
	MPDZ	NM_001330637.2		c.2580A>G	p.Leu860Leu	synonymous	Exon 19 of 47	NP_001317566.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	ENST00000319217.12	TSL:5 MANE Select	c.2580A>G	p.Leu860Leu	synonymous	Exon 19 of 47	ENSP00000320006.7
	MPDZ	ENST00000541718.5	TSL:1	c.2580A>G	p.Leu860Leu	synonymous	Exon 19 of 46	ENSP00000439807.1
	MPDZ	ENST00000447879.6	TSL:1	c.2580A>G	p.Leu860Leu	synonymous	Exon 19 of 46	ENSP00000415208.1

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00467

Gnomad ASJ AF: 0.00894

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00629

Gnomad OTH AF: 0.00671

GnomAD2 exomes AF: 0.00440 AC: 1089 AN: 247636 AF XY: 0.00451

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00918

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000559

Gnomad NFE exome AF: 0.00644

Gnomad OTH exome AF: 0.00634

GnomAD4 exome AF: 0.00600 AC: 8767 AN: 1460334 Hom.: 39 Cov.: 31 AF XY: 0.00594 AC XY: 4318 AN XY: 726430

African (AFR) AF: 0.000928 AC: 31 AN: 33416

American (AMR) AF: 0.00350 AC: 156 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00851 AC: 222 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00354 AC: 305 AN: 86176

European-Finnish (FIN) AF: 0.000769 AC: 41 AN: 53348

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5758

European-Non Finnish (NFE) AF: 0.00680 AC: 7556 AN: 1111146

Other (OTH) AF: 0.00650 AC: 392 AN: 60294

GnomAD4 genome AF: 0.00404 AC: 614 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.00382 AC XY: 284 AN XY: 74348

African (AFR) AF: 0.00125 AC: 52 AN: 41544

American (AMR) AF: 0.00466 AC: 71 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00894 AC: 31 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4820

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00629 AC: 427 AN: 67928

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.00470 Hom.: 1

Bravo AF: 0.00487

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.00873

EpiControl AF: 0.00667

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
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.2
DANN	Benign	0.80
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34704118; hg19: chr9-13183486;