3-52689102-A-G

Variant names:

• chr3-52689102-A-G
• rs2097324911
• NM_014366.5:c.437A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014366.5(GNL3):​c.437A>G​(p.Glu146Gly) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNL3 NM_014366.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.91

Genes affected

GNL3 (HGNC:29931): (G protein nucleolar 3) The protein encoded by this gene may interact with p53 and may be involved in tumorigenesis. The encoded protein also appears to be important for stem cell proliferation. This protein is found in both the nucleus and nucleolus. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

SNORD19 (HGNC:32717): (small nucleolar RNA, C/D box 19)

ENSG00000252787 (HGNC:):

SNORD136 (HGNC:50417): (small nucleolar RNA, C/D box 136)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNL3	NM_014366.5	c.437A>G	p.Glu146Gly	missense_variant	Exon 6 of 15	ENST00000418458.6	NP_055181.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNL3	ENST00000418458.6	c.437A>G	p.Glu146Gly	missense_variant	Exon 6 of 15	1	NM_014366.5	ENSP00000395772.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.437A>G (p.E146G) alteration is located in exon 6 (coding exon 6) of the GNL3 gene. This alteration results from a A to G substitution at nucleotide position 437, causing the glutamic acid (E) at amino acid position 146 to be replaced by a glycine (G). 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	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.8	.;H;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.77, 0.75
MutPred		0.56		.;Loss of stability (P = 0.0265);.;
MVP		0.83
MPC		0.55
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2097324911; hg19: chr3-52723118;