3-52693805-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014366.5(GNL3):​c.1498G>A​(p.Asp500Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GNL3
NM_014366.5 missense, splice_region

Scores

19
Splicing: ADA: 0.00008461
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.735
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.053819984).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GNL3NM_014366.5 linkuse as main transcriptc.1498G>A p.Asp500Asn missense_variant, splice_region_variant 13/15 ENST00000418458.6 NP_055181.3
GNL3NM_206825.2 linkuse as main transcriptc.1462G>A p.Asp488Asn missense_variant, splice_region_variant 13/15 NP_996561.1
GNL3NM_206826.1 linkuse as main transcriptc.1462G>A p.Asp488Asn missense_variant, splice_region_variant 13/15 NP_996562.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GNL3ENST00000418458.6 linkuse as main transcriptc.1498G>A p.Asp500Asn missense_variant, splice_region_variant 13/151 NM_014366.5 ENSP00000395772 P2Q9BVP2-1
GNL3ENST00000394799.6 linkuse as main transcriptc.1462G>A p.Asp488Asn missense_variant, splice_region_variant 13/152 ENSP00000378278 A2Q9BVP2-2
GNL3ENST00000496254.5 linkuse as main transcriptn.1782G>A splice_region_variant, non_coding_transcript_exon_variant 12/145
GNL3ENST00000497356.1 linkuse as main transcript downstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1459438
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
726212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000370
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 05, 2023The c.1498G>A (p.D500N) alteration is located in exon 13 (coding exon 13) of the GNL3 gene. This alteration results from a G to A substitution at nucleotide position 1498, causing the aspartic acid (D) at amino acid position 500 to be replaced by an asparagine (N). 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
0.069
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.77
CADD
Benign
7.8
DANN
Benign
0.89
DEOGEN2
Benign
0.056
T;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.46
T;T
M_CAP
Benign
0.0060
T
MetaRNN
Benign
0.054
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.35
N;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-0.36
N;N
REVEL
Benign
0.040
Sift
Benign
0.46
T;T
Sift4G
Benign
0.73
T;T
Polyphen
0.0
B;.
Vest4
0.081
MVP
0.20
MPC
0.097
ClinPred
0.036
T
GERP RS
-1.0
Varity_R
0.028
gMVP
0.11

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000085
dbscSNV1_RF
Benign
0.030
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs780896442; hg19: chr3-52727821; API