6-30555147-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005275.5(GNL1):c.284G>A(p.Arg95Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,460,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GNL1 NM_005275.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.802

Genes affected

GNL1 (HGNC:4413): (G protein nucleolar 1 (putative)) The GNL1 gene, identified in the human major histocompatibility complex class I region, shows a high degree of similarity with its mouse counterpart. The GNL1 gene is located less than 2 kb centromeric to HLA-E, in the same transcriptional orientation. GNL1 is telomeric to HLA-B and HLA-C. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039464593).
• BS2: High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNL1	NM_005275.5	c.284G>A	p.Arg95Lys	missense_variant	3/12	ENST00000376621.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNL1	ENST00000376621.8	c.284G>A	p.Arg95Lys	missense_variant	3/12	1	NM_005275.5	P1
GNL1	ENST00000433809.1	c.278G>A	p.Arg93Lys	missense_variant	2/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000324 AC: 8 AN: 247118 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134610

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000328

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1460766 Hom.: 0 Cov.: 33 AF XY: 0.00000826 AC XY: 6 AN XY: 726694

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000843 AC: 1

Asia WGS AF: 0.00144 AC: 5 AN: 3478

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

Feb 15, 2023

The c.284G>A (p.R95K) alteration is located in exon 3 (coding exon 3) of the GNL1 gene. This alteration results from a G to A substitution at nucleotide position 284, causing the arginine (R) at amino acid position 95 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	0.090
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	15
Dann	Benign	0.93
DEOGEN2	Benign	0.0079	T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.039	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	0.60	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.049
Sift	Benign	0.96	T;T
Sift4G	Benign	0.99	T;T
Polyphen		0.0	B;.
Vest4		0.12
MutPred		0.30		Gain of ubiquitination at R95 (P = 0.0054);.;
MVP		0.33
MPC		0.66
ClinPred		0.055	T
GERP RS		3.8
Varity_R		0.14
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs373241512; hg19: chr6-30522924;