12-41188847-G-A

Position:

• chr12-41188847-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164595.2(PDZRN4):​c.392G>A​(p.Gly131Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000269 in 1,114,440 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: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PDZRN4 NM_001164595.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.294

Genes affected

PDZRN4 (HGNC:30552): (PDZ domain containing ring finger 4) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07259068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZRN4	NM_001164595.2	c.392G>A	p.Gly131Glu	missense_variant	1/10	ENST00000402685.7	NP_001158067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDZRN4	ENST00000402685.7	c.392G>A	p.Gly131Glu	missense_variant	1/10	2	NM_001164595.2	ENSP00000384197.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000269 AC: 3 AN: 1114440 Hom.: 0 Cov.: 30 AF XY: 0.00000376 AC XY: 2 AN XY: 531246

Gnomad4 AFR exome AF: 0.00

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: 0.00000320

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2024

The c.392G>A (p.G131E) alteration is located in exon 1 (coding exon 1) of the PDZRN4 gene. This alteration results from a G to A substitution at nucleotide position 392, causing the glycine (G) at amino acid position 131 to be replaced by a glutamic acid (E). 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	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.1
DANN	Benign	0.94
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.34	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	0.84	N
REVEL	Benign	0.033
Sift	Benign	0.47	T
Sift4G	Benign	1.0	T
Vest4		0.098
MutPred		0.33		Gain of solvent accessibility (P = 0.0145);
MVP		0.30
MPC		1.1
ClinPred		0.062	T
GERP RS		-0.51
Varity_R		0.038
gMVP		0.11

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: rs1247232167; hg19: chr12-41582649;