Variant 1-145673878-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001201325.2(PDZK1):c.994C>T(p.His332Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00086 ( 1 hom., cov: 25)

Exomes 𝑓: 0.00064 ( 6 hom. )

Failed GnomAD Quality Control

Consequence

PDZK1
NM_001201325.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.946

Variant links:

Genes affected

PDZK1 (HGNC:8821): (PDZ domain containing 1) This gene encodes a PDZ domain-containing scaffolding protein. PDZ domain-containing molecules bind to and mediate the subcellular localization of target proteins. The encoded protein mediates the localization of cell surface proteins and plays a critical role in cholesterol metabolism by regulating the HDL receptor, scavenger receptor class B type 1. Single nucleotide polymorphisms in this gene may be associated with metabolic syndrome, and overexpression of this gene may play a role in drug resistance of multiple myeloma. Pseudogenes of this gene are located on the long arm of chromosome 1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

PDZK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08280113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZK1	NM_001201325.2 linkuse as main transcript	c.994C>T	p.His332Tyr	missense_variant	7/9	ENST00000417171.6	NP_001188254.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDZK1	ENST00000417171.6 linkuse as main transcript	c.994C>T	p.His332Tyr	missense_variant	7/9	1	NM_001201325.2	ENSP00000394485	P1	Q5T2W1-1
PDZK1	ENST00000344770.6 linkuse as main transcript	c.994C>T	p.His332Tyr	missense_variant	7/9	5		ENSP00000342143	P1	Q5T2W1-1
PDZK1	ENST00000451928.6 linkuse as main transcript	c.661C>T	p.His221Tyr	missense_variant	5/7	2		ENSP00000403422		Q5T2W1-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

122

AN:

143720

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000781

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000143

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000522

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00170

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000554

AC:

AN:

55980

Hom.:

AF XY:

0.000636

AC XY:

AN XY:

28324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000186

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00103

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000635

AC:

880

AN:

1385434

Hom.:

Cov.:

AF XY:

0.000683

AC XY:

473

AN XY:

692628

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.000398

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000432

Gnomad4 NFE exome

AF:

0.000770

Gnomad4 OTH exome

AF:

0.000537

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000855

AC:

123

AN:

143826

Hom.:

Cov.:

AF XY:

0.000747

AC XY:

AN XY:

69602

show subpopulations

Gnomad4 AFR

AF:

0.000104

Gnomad4 AMR

AF:

0.000142

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000522

Gnomad4 NFE

AF:

0.00170

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00279

Hom.:

Bravo

AF:

0.000567

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2022

The c.994C>T (p.H332Y) alteration is located in exon 8 (coding exon 6) of the PDZK1 gene. This alteration results from a C to T substitution at nucleotide position 994, causing the histidine (H) at amino acid position 332 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.21

.;T;T

LIST_S2

Benign

0.83

T;T;.

MetaRNN

Benign

0.083

T;T;T

PROVEAN

Benign

-0.88

N;N;N

Sift

Benign

0.062

T;T;T

Sift4G

Benign

0.10

T;T;T

Vest4

0.19

gMVP

0.21

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over