chrX-54551914-A-G

Variant names:

• chrX-54551914-A-G
• NM_001184819.2:c.1121A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001184819.2(GNL3L):​c.1121A>G​(p.Lys374Arg) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: GNL3L NM_001184819.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.11
• Publications: 0 publications found

Genes affected

GNL3L (HGNC:25553): (G protein nucleolar 3 like) The protein encoded by this gene appears to be a nucleolar GTPase that is essential for ribosomal pre-rRNA processing and cell proliferation. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09487265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNL3L	NM_001184819.2	c.1121A>G	p.Lys374Arg	missense_variant	Exon 12 of 16	ENST00000360845.3	NP_001171748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNL3L	ENST00000360845.3	c.1121A>G	p.Lys374Arg	missense_variant	Exon 12 of 16	5	NM_001184819.2	ENSP00000354091.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1121A>G (p.K374R) alteration is located in exon 12 (coding exon 11) of the GNL3L gene. This alteration results from a A to G substitution at nucleotide position 1121, causing the lysine (K) at amino acid position 374 to be replaced by an arginine (R). 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	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;T
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.095	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		3.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.085
Sift	Benign	0.54	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.047	B;B
Vest4		0.11
MutPred		0.27		Loss of ubiquitination at K374 (P = 0.0546);Loss of ubiquitination at K374 (P = 0.0546);
MVP		0.64
MPC		0.31
ClinPred		0.72	D
GERP RS		4.2
Varity_R		0.27
gMVP		0.57
Mutation Taster		=93/7	polymorphism

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

hg19: chrX-54578347;