9-13189018-T-C

Variant names:

• chr9-13189018-T-C
• rs41265290
• NM_001378778.1:c.2155-25A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001378778.1(MPDZ):​c.2155-25A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,593,518 control chromosomes in the GnomAD database, including 244 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.013 (27 hom., cov: 32)
  • Exomes 𝑓: 0.015 (217 hom.)
• Consequence: MPDZ NM_001378778.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.213
• Publications: 3 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0127 (1925/152138) while in subpopulation AMR AF = 0.0173 (264/15264). AF 95% confidence interval is 0.0163. There are 27 homozygotes in GnomAd4. There are 927 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	NM_001378778.1	MANE Select	c.2155-25A>G		intron	N/A	NP_001365707.1
	MPDZ	NM_001375413.1		c.2155-25A>G		intron	N/A	NP_001362342.1
	MPDZ	NM_001330637.2		c.2155-25A>G		intron	N/A	NP_001317566.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPDZ	ENST00000319217.12	TSL:5 MANE Select	c.2155-25A>G		intron	N/A	ENSP00000320006.7
	MPDZ	ENST00000541718.5	TSL:1	c.2155-25A>G		intron	N/A	ENSP00000439807.1
	MPDZ	ENST00000447879.6	TSL:1	c.2155-25A>G		intron	N/A	ENSP00000415208.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1927 AN: 152020 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0173

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0137 AC: 3257 AN: 237858 AF XY: 0.0140

Gnomad AFR exome AF: 0.00239

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0147

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.0154 AC: 22197 AN: 1441380 Hom.: 217 Cov.: 27 AF XY: 0.0154 AC XY: 11046 AN XY: 715788

African (AFR) AF: 0.00310 AC: 102 AN: 32914

American (AMR) AF: 0.0122 AC: 530 AN: 43538

Ashkenazi Jewish (ASJ) AF: 0.0439 AC: 1126 AN: 25634

East Asian (EAS) AF: 0.00 AC: 0 AN: 39278

South Asian (SAS) AF: 0.00450 AC: 380 AN: 84512

European-Finnish (FIN) AF: 0.0125 AC: 657 AN: 52490

Middle Eastern (MID) AF: 0.0319 AC: 181 AN: 5674

European-Non Finnish (NFE) AF: 0.0166 AC: 18185 AN: 1097882

Other (OTH) AF: 0.0174 AC: 1036 AN: 59458

GnomAD4 genome AF: 0.0127 AC: 1925 AN: 152138 Hom.: 27 Cov.: 32 AF XY: 0.0125 AC XY: 927 AN XY: 74348

African (AFR) AF: 0.00340 AC: 141 AN: 41528

American (AMR) AF: 0.0173 AC: 264 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10590

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0171 AC: 1166 AN: 67996

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.0160 Hom.: 35

Bravo AF: 0.0129

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.71
PhyloP100		0.21
La Branchor		0.84
BranchPoint Hunter		6.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs41265290; hg19: chr9-13189017;