12-110457525-C-T

Variant names:

• chr12-110457525-C-T
• NM_016301.4:c.435G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016301.4(GPN3):​c.435G>A​(p.Met145Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. M145V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GPN3 NM_016301.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27
• Publications: 0 publications found

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]

ENSG00000300534 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37380433).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016301.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPN3	NM_016301.4	MANE Select	c.435G>A	p.Met145Ile	missense	Exon 4 of 8	NP_057385.3
	GPN3	NM_001164372.2		c.552G>A	p.Met184Ile	missense	Exon 4 of 8	NP_001157844.1	Q9UHW5-3
	GPN3	NM_001164373.2		c.465G>A	p.Met155Ile	missense	Exon 4 of 8	NP_001157845.1	Q9UHW5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPN3	ENST00000228827.8	TSL:1 MANE Select	c.435G>A	p.Met145Ile	missense	Exon 4 of 8	ENSP00000228827.3	Q9UHW5-1
	GPN3	ENST00000537466.6	TSL:1	c.465G>A	p.Met155Ile	missense	Exon 4 of 8	ENSP00000443068.2	Q9UHW5-2
	GPN3	ENST00000543199.5	TSL:5	c.552G>A	p.Met184Ile	missense	Exon 4 of 8	ENSP00000442770.1	Q9UHW5-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.043	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.43	T
Sift4G	Benign	1.0	T
Polyphen		0.094	B
Vest4		0.75
MutPred		0.53		Gain of catalytic residue at Q143 (P = 0.0011)
MVP		0.39
MPC		0.31
ClinPred		0.71	D
GERP RS		5.8
Varity_R		0.40
gMVP		0.70
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr12-110895330;