Genetic Variant PDZK1:c.-69T>C (chr1-145707383-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002614.4(PDZK1):c.-140T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 152,462 control chromosomes in the GnomAD database, including 67,579 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.

Frequency

Genomes: 𝑓 0.94 ( 67518 hom., cov: 34)

Exomes 𝑓: 0.94 ( 61 hom. )

Consequence

PDZK1
NM_002614.4 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.98

Publications

30 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002614.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDZK1	NM_002614.4		c.-140T>C	5_prime_UTR	Exon 1 of 10	NP_002605.2	Q5T2W1-1
PDZK1	NM_001201326.1		c.-69T>C	5_prime_UTR	Exon 1 of 7	NP_001188255.1	Q5T2W1-2
PDZK1	NM_001201325.2	MANE Select	c.-69T>C	upstream_gene	N/A	NP_001188254.1	Q5T2W1-1

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
PDZK1	ENST00000960532.1	c.-69T>C	5_prime_UTR	Exon 1 of 11	ENSP00000630591.1
PDZK1	ENST00000907412.1	c.-140T>C	5_prime_UTR	Exon 1 of 12	ENSP00000577471.1
PDZK1	ENST00000907408.1	c.-370T>C	5_prime_UTR	Exon 1 of 10	ENSP00000577467.1

Frequencies

GnomAD3 genomes

AF:

0.941

AC:

143166

AN:

152208

Hom.:

67463

Cov.:

show subpopulations

Gnomad AFR

AF:

0.963

Gnomad AMI

AF:

0.999

Gnomad AMR

AF:

0.952

Gnomad ASJ

AF:

0.953

Gnomad EAS

AF:

0.835

Gnomad SAS

AF:

0.776

Gnomad FIN

AF:

0.960

Gnomad MID

AF:

0.953

Gnomad NFE

AF:

0.939

Gnomad OTH

AF:

0.950

GnomAD4 exome

AF:

0.941

AC:

128

AN:

136

Hom.:

Cov.:

AF XY:

0.957

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AF:

1.00

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.934

AC:

AN:

106

Other (OTH)

AF:

0.875

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.941

AC:

143280

AN:

152326

Hom.:

67518

Cov.:

AF XY:

0.939

AC XY:

69949

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.963

AC:

40051

AN:

41570

American (AMR)

AF:

0.952

AC:

14580

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.953

AC:

3310

AN:

3472

East Asian (EAS)

AF:

0.835

AC:

4325

AN:

5182

South Asian (SAS)

AF:

0.775

AC:

3736

AN:

4820

European-Finnish (FIN)

AF:

0.960

AC:

10201

AN:

10626

Middle Eastern (MID)

AF:

0.949

AC:

279

AN:

294

European-Non Finnish (NFE)

AF:

0.939

AC:

63879

AN:

68030

Other (OTH)

AF:

0.951

AC:

2008

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

439

877

1316

1754

2193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.939

Hom.:

232238

Bravo

AF:

0.945

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

PhyloP100

2.0

PromoterAI

0.026

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over