chr3-73383995-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS2_Supporting

The NM_015009.3(PDZRN3):​c.2571C>A​(p.Ser857Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S857N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

PDZRN3
NM_015009.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.147
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04032728).
BS2
High AC in GnomAdExome4 at 5 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/exons MANE UniProt
PDZRN3NM_015009.3 linkuse as main transcriptc.2571C>A p.Ser857Arg missense_variant 10/10 ENST00000263666.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PDZRN3ENST00000263666.9 linkuse as main transcriptc.2571C>A p.Ser857Arg missense_variant 10/101 NM_015009.3 P1Q9UPQ7-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000174
AC:
4
AN:
229312
Hom.:
0
AF XY:
0.0000162
AC XY:
2
AN XY:
123494
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000926
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000555
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:
0.00000348
AC:
5
AN:
1437202
Hom.:
0
Cov.:
31
AF XY:
0.00000421
AC XY:
3
AN XY:
712964
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000703
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.07e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingAmbry GeneticsOct 03, 2022The c.2571C>A (p.S857R) alteration is located in exon 10 (coding exon 10) of the PDZRN3 gene. This alteration results from a C to A substitution at nucleotide position 2571, causing the serine (S) at amino acid position 857 to be replaced by an arginine (R). 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
0.31
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
5.1
DANN
Benign
0.66
DEOGEN2
Benign
0.027
T;.;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.68
T;.;T;T
M_CAP
Benign
0.0071
T
MetaRNN
Benign
0.040
T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.53
N;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
0.42
N;N;N;N
REVEL
Benign
0.068
Sift
Benign
0.53
T;T;T;T
Sift4G
Benign
0.54
T;T;T;T
Polyphen
0.0
B;.;.;B
Vest4
0.19
MutPred
0.23
Gain of MoRF binding (P = 0.0075);.;.;.;
MVP
0.13
MPC
0.22
ClinPred
0.0094
T
GERP RS
-0.031
Varity_R
0.036
gMVP
0.17

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.

Other links and lift over

dbSNP: rs530854246; hg19: chr3-73433146; API