14-30593527-G-A

Position:

• chr14-30593527-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017769.5(G2E3):​c.416G>A​(p.Arg139Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: G2E3 NM_017769.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

Genes affected

G2E3 (HGNC:20338): (G2/M-phase specific E3 ubiquitin protein ligase) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in apoptotic process and protein ubiquitination. Predicted to act upstream of or within blastocyst development; negative regulation of intrinsic apoptotic signaling pathway; and protein polyubiquitination. Located in Golgi apparatus and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

G2E3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053020746).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G2E3	NM_017769.5	c.416G>A	p.Arg139Lys	missense_variant	6/15	ENST00000206595.11	NP_060239.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G2E3	ENST00000206595.11	c.416G>A	p.Arg139Lys	missense_variant	6/15	1	NM_017769.5	ENSP00000206595.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 32

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 15, 2024

The c.416G>A (p.R139K) alteration is located in exon 6 (coding exon 5) of the G2E3 gene. This alteration results from a G to A substitution at nucleotide position 416, causing the arginine (R) at amino acid position 139 to be replaced by a lysine (K). 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	0.079
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Benign	0.021	T;T;T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.053	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.52	N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.73	T;T;T;T
Sift4G	Benign	0.94	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.070
MutPred		0.46		Gain of catalytic residue at P143 (P = 8e-04);.;.;Gain of catalytic residue at P143 (P = 8e-04);
MVP		0.24
MPC		0.31
ClinPred		0.034	T
GERP RS		0.97
Varity_R		0.024
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-31062733;