3-73624208-C-G

Variant names:

• chr3-73624208-C-G
• rs927416765
• NM_015009.3:c.618G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015009.3(PDZRN3):​c.618G>C​(p.Gln206His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000599 in 1,336,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000060 (0 hom.)
• Consequence: PDZRN3 NM_015009.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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

ENSG00000278934 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11097759).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZRN3	NM_015009.3	c.618G>C	p.Gln206His	missense_variant	Exon 1 of 10	ENST00000263666.9	NP_055824.1
PDZRN3	XM_017005942.3	c.618G>C	p.Gln206His	missense_variant	Exon 1 of 9		XP_016861431.1
PDZRN3-AS1	NR_046681.1	n.398+243C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDZRN3	ENST00000263666.9	c.618G>C	p.Gln206His	missense_variant	Exon 1 of 10	1	NM_015009.3	ENSP00000263666.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000599 AC: 8 AN: 1336578 Hom.: 0 Cov.: 30 AF XY: 0.00000607 AC XY: 4 AN XY: 658722

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000325

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.45e-7

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.618G>C (p.Q206H) alteration is located in exon 1 (coding exon 1) of the PDZRN3 gene. This alteration results from a G to C substitution at nucleotide position 618, causing the glutamine (Q) at amino acid position 206 to be replaced by a histidine (H). 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	0.30
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.64	N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.041
Sift	Benign	0.26	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.0020	B;.
Vest4		0.13
MutPred		0.38		Loss of helix (P = 0.0123);Loss of helix (P = 0.0123);
MVP		0.36
MPC		1.3
ClinPred		0.14	T
GERP RS		3.2
Varity_R		0.13
gMVP		0.45

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

Other links and lift over

dbSNP: rs927416765; hg19: chr3-73673359;