Genetic Variant GNL3:p.Gly266Val (chr3-52691557-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014366.5(GNL3):c.797G>T(p.Gly266Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,435,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. G266E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

GNL3
NM_014366.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.60

Publications

0 publications found

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]

GNL3 links:

SNORD19C (HGNC:52224): (small nucleolar RNA, C/D box 19C)

SNORD19C links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014366.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNL3	NM_014366.5	MANE Select	c.797G>T	p.Gly266Val	missense	Exon 9 of 15	NP_055181.3
GNL3	NM_206825.2		c.761G>T	p.Gly254Val	missense	Exon 9 of 15	NP_996561.1	Q9BVP2-2
GNL3	NM_206826.1		c.761G>T	p.Gly254Val	missense	Exon 9 of 15	NP_996562.1	Q9BVP2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNL3	ENST00000418458.6	TSL:1 MANE Select	c.797G>T	p.Gly266Val	missense	Exon 9 of 15	ENSP00000395772.1	Q9BVP2-1
GNL3	ENST00000858565.1		c.794G>T	p.Gly265Val	missense	Exon 9 of 15	ENSP00000528624.1
GNL3	ENST00000931677.1		c.797G>T	p.Gly266Val	missense	Exon 9 of 15	ENSP00000601736.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000279

AC:

AN:

1435540

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

715342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32848

American (AMR)

AF:

0.00

AC:

AN:

43996

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25924

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.00

AC:

AN:

84260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00000367

AC:

AN:

1090360

Other (OTH)

AF:

0.00

AC:

AN:

59512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

PhyloP100

9.6

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-9.0

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.95

Loss of ubiquitination at K267 (P = 0.0714)

MVP

0.99

MPC

0.57

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.89

Mutation Taster

=28/72

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over