12-110457595-T-C

Position:

• chr12-110457595-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016301.4(GPN3):​c.365A>G​(p.Gln122Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,456,028 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: GPN3 NM_016301.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

Genes affected

GPN3 (HGNC:30186): (GPN-loop GTPase 3) Predicted to enable GTPase activity. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2839728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPN3	NM_016301.4	c.365A>G	p.Gln122Arg	missense_variant	4/8	ENST00000228827.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPN3	ENST00000228827.8	c.365A>G	p.Gln122Arg	missense_variant	4/8	1	NM_016301.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249392 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135012

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000886

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: 0.000329

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1456028 Hom.: 0 Cov.: 29 AF XY: 0.00000690 AC XY: 5 AN XY: 724786

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000681

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: 0.0000333

GnomAD4 genome Cov.: 31

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.00000378

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

Sep 17, 2021

The c.482A>G (p.Q161R) alteration is located in exon 4 (coding exon 4) of the GPN3 gene. This alteration results from a A to G substitution at nucleotide position 482, causing the glutamine (Q) at amino acid position 161 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	T;.;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.99	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.34	T;T;T;T
Sift4G	Benign	0.76	T;T;T;T
Polyphen		0.0050	B;.;B;.
Vest4		0.55
MutPred		0.41		Loss of ubiquitination at K121 (P = 0.047);.;.;.;
MVP		0.33
MPC		0.22
ClinPred		0.18	T
GERP RS		5.8
Varity_R		0.35
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1313516117; hg19: chr12-110895400;