12-110459811-C-G

Variant names:

• chr12-110459811-C-G
• rs748305243
• NM_016301.4:c.209G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016301.4(GPN3):​c.209G>C​(p.Arg70Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GPN3 NM_016301.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.85
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.209G>C	p.Arg70Pro	missense	Exon 3 of 8	NP_057385.3
	GPN3	NM_001164372.2		c.326G>C	p.Arg109Pro	missense	Exon 3 of 8	NP_001157844.1	Q9UHW5-3
	GPN3	NM_001164373.2		c.239G>C	p.Arg80Pro	missense	Exon 3 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.209G>C	p.Arg70Pro	missense	Exon 3 of 8	ENSP00000228827.3	Q9UHW5-1
	GPN3	ENST00000537466.6	TSL:1	c.239G>C	p.Arg80Pro	missense	Exon 3 of 8	ENSP00000443068.2	Q9UHW5-2
	GPN3	ENST00000543199.5	TSL:5	c.326G>C	p.Arg109Pro	missense	Exon 3 of 8	ENSP00000442770.1	Q9UHW5-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461554 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727120

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111698

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.9
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.16
Sift	Benign	0.22	T
Sift4G	Benign	0.25	T
Polyphen		0.82	P
Vest4		0.64
MutPred		0.46		Gain of catalytic residue at N74 (P = 0)
MVP		0.45
MPC		0.75
ClinPred		0.96	D
GERP RS		4.1
PromoterAI		-0.017	Neutral
Varity_R		0.49
gMVP		0.90

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

Other links and lift over

dbSNP: rs748305243; hg19: chr12-110897616;