chr9-13158063-C-T

Variant names:

• chr9-13158063-C-T
• rs41265286
• NM_001378778.1:c.3407G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001378778.1(MPDZ):​c.3407G>A​(p.Ser1136Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,612,790 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. S1136S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (9 hom.)
• Consequence: MPDZ NM_001378778.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.70
• Publications: 9 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006310791).
• BP6: Variant 9-13158063-C-T is Benign according to our data. Variant chr9-13158063-C-T is described in ClinVar as Benign. ClinVar VariationId is 740408.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00207 (315/152238) while in subpopulation NFE AF = 0.00184 (125/68016). AF 95% confidence interval is 0.00158. There are 1 homozygotes in GnomAd4. There are 199 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.3407G>A	p.Ser1136Asn	missense	Exon 24 of 47	NP_001365707.1	O75970-1
	MPDZ	NM_001375413.1		c.3407G>A	p.Ser1136Asn	missense	Exon 24 of 48	NP_001362342.1
	MPDZ	NM_001330637.2		c.3407G>A	p.Ser1136Asn	missense	Exon 24 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.3407G>A	p.Ser1136Asn	missense	Exon 24 of 47	ENSP00000320006.7	O75970-1
	MPDZ	ENST00000541718.5	TSL:1	c.3407G>A	p.Ser1136Asn	missense	Exon 24 of 46	ENSP00000439807.1	O75970-2
	MPDZ	ENST00000447879.6	TSL:1	c.3407G>A	p.Ser1136Asn	missense	Exon 24 of 46	ENSP00000415208.1	O75970-3

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 315 AN: 152120 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00223 AC: 554 AN: 248442 AF XY: 0.00221

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.00231

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00201 AC: 2934 AN: 1460552 Hom.: 9 Cov.: 30 AF XY: 0.00192 AC XY: 1397 AN XY: 726532

African (AFR) AF: 0.000269 AC: 9 AN: 33432

American (AMR) AF: 0.000358 AC: 16 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86200

European-Finnish (FIN) AF: 0.0103 AC: 551 AN: 53352

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.00200 AC: 2219 AN: 1111182

Other (OTH) AF: 0.00216 AC: 130 AN: 60302

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152238 Hom.: 1 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74408

African (AFR) AF: 0.000505 AC: 21 AN: 41566

American (AMR) AF: 0.000655 AC: 10 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0149 AC: 158 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68016

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00165 Hom.: 0

Bravo AF: 0.00114

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00106 AC: 4

ESP6500EA AF: 0.00182 AC: 15

ExAC AF: 0.00229 AC: 276

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.50
ClinPred		0.035	T
GERP RS		5.9
Varity_R		0.30
gMVP		0.47
Mutation Taster		=88/12	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: rs41265286; hg19: chr9-13158062; COSMIC: COSV105182814;