Genetic Variant PDZRN3:p.Ala115Thr (chr3-73624483-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015009.3(PDZRN3):c.343G>A(p.Ala115Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,404,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

PDZRN3
NM_015009.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09127188).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PDZRN3	NM_015009.3 link	c.343G>A	p.Ala115Thr	missense_variant	Exon 1 of 10	ENST00000263666.9	NP_055824.1
PDZRN3	XM_017005942.3 link	c.343G>A	p.Ala115Thr	missense_variant	Exon 1 of 9		XP_016861431.1
PDZRN3-AS1	NR_046681.1 link	n.398+518C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDZRN3	ENST00000263666.9 link	c.343G>A	p.Ala115Thr	missense_variant	Exon 1 of 10	1	NM_015009.3	ENSP00000263666.4		Q9UPQ7-1

Frequencies

GnomAD3 genomes

AF:

0.0000857

AC:

AN:

151628

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1252944

Hom.:

Cov.:

AF XY:

0.00000653

AC XY:

AN XY:

612320

show subpopulations

Gnomad4 AFR exome

AF:

0.000242

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000196

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000857

AC:

AN:

151736

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74164

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ExAC

AF:

0.0000696

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.343G>A (p.A115T) alteration is located in exon 1 (coding exon 1) of the PDZRN3 gene. This alteration results from a G to A substitution at nucleotide position 343, causing the alanine (A) at amino acid position 115 to be replaced by a threonine (T). 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

0.097

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.018

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.091

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.11

N;N

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.14

N;N

REVEL

Benign

0.066

Sift

Benign

0.27

T;T

Sift4G

Benign

0.32

T;T

Polyphen

0.54

P;.

Vest4

0.15

MutPred

0.27

Gain of phosphorylation at A115 (P = 0.0275);Gain of phosphorylation at A115 (P = 0.0275);

MVP

0.31

MPC

1.5

ClinPred

0.20

GERP RS

0.65

Varity_R

0.078

gMVP

0.28

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