Genetic Variant PDZRN3:p.Gly118Cys (chr3-73624474-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_015009.3(PDZRN3):c.352G>T(p.Gly118Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000574 in 1,393,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PDZRN3
NM_015009.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.308

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1143783).

BS2

High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PDZRN3	NM_015009.3 link	c.352G>T	p.Gly118Cys	missense_variant	Exon 1 of 10	ENST00000263666.9	NP_055824.1
PDZRN3	XM_017005942.3 link	c.352G>T	p.Gly118Cys	missense_variant	Exon 1 of 9		XP_016861431.1
PDZRN3-AS1	NR_046681.1 link	n.398+509C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDZRN3	ENST00000263666.9 link	c.352G>T	p.Gly118Cys	missense_variant	Exon 1 of 10	1	NM_015009.3	ENSP00000263666.4		Q9UPQ7-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151584

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

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

GnomAD3 exomes

AF:

0.000183

AC:

AN:

21898

Hom.:

AF XY:

0.0000763

AC XY:

AN XY:

13106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000483

AC:

AN:

1241696

Hom.:

Cov.:

AF XY:

0.00000495

AC XY:

AN XY:

606126

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000468

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151584

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74030

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.352G>T (p.G118C) alteration is located in exon 1 (coding exon 1) of the PDZRN3 gene. This alteration results from a G to T substitution at nucleotide position 352, causing the glycine (G) at amino acid position 118 to be replaced by a cysteine (C). 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

0.23

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

T;.

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.68

T;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.65

N;D

REVEL

Benign

0.15

Sift

Uncertain

0.026

D;D

Sift4G

Benign

0.067

T;D

Polyphen

0.98

D;.

Vest4

0.15

MutPred

0.48

Loss of MoRF binding (P = 0.097);Loss of MoRF binding (P = 0.097);

MVP

0.42

MPC

1.6

ClinPred

0.13

GERP RS

2.6

Varity_R

0.17

gMVP

0.44

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