Genetic Variant PDZRN3:p.His22Leu (chr3-73624761-T-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_015009.3(PDZRN3):c.65A>T(p.His22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,493,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H22R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PDZRN3
NM_015009.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.11

Publications

0 publications found

Variant links:

Genes affected

PDZRN3 (HGNC:17704): (PDZ domain containing ring finger 3) This gene encodes a member of the LNX (Ligand of Numb Protein-X) family of RING-type ubiquitin E3 ligases. This protein may function in vascular morphogenesis and the differentiation of adipocytes, osteoblasts and myoblasts. This protein may be targeted for degradation by the human papilloma virus E6 protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

PDZRN3 links:

ENSG00000278934 (HGNC:):

ENSG00000278934 links:

PDZRN3-AS1 (HGNC:40814): (PDZRN3 antisense RNA 1)

PDZRN3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0088222325).

BS2

High AC in GnomAdExome4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015009.3. 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
	PDZRN3	NM_015009.3	MANE Select	c.65A>T	p.His22Leu	missense	Exon 1 of 10	NP_055824.1	Q9UPQ7-1
	PDZRN3-AS1	NR_046681.1		n.399-651T>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PDZRN3	ENST00000263666.9	TSL:1 MANE Select	c.65A>T	p.His22Leu	missense	Exon 1 of 10	ENSP00000263666.4	Q9UPQ7-1
PDZRN3	ENST00000308537.4	TSL:1	c.65A>T	p.His22Leu	missense	Exon 1 of 4	ENSP00000308831.4	Q9UPQ7-2
ENSG00000278934	ENST00000625169.1	TSL:6	n.352T>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000778

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000166

AC:

AN:

132192

AF XY:

0.000160

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00288

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000149

AC:

AN:

1341176

Hom.:

Cov.:

AF XY:

0.0000121

AC XY:

AN XY:

663592

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27958

American (AMR)

AF:

0.00

AC:

AN:

30398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22536

East Asian (EAS)

AF:

0.000608

AC:

AN:

31232

South Asian (SAS)

AF:

0.00

AC:

AN:

72008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5248

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1060902

Other (OTH)

AF:

0.0000180

AC:

AN:

55450

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000263

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41548

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000780

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67970

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000137

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.024

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.0088

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.91

PhyloP100

1.1

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.98

REVEL

Benign

0.058

Sift

Benign

0.16

Sift4G

Benign

0.78

Polyphen

0.080

Vest4

0.14

MVP

0.31

MPC

1.7

ClinPred

0.078

GERP RS

3.0

PromoterAI

0.012

Neutral

(source)

Varity_R

0.22

gMVP

0.41

Mutation Taster

=83/17

polymorphism

(source)

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

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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