6-30553141-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005275.5(GNL1):c.847C>T(p.Arg283Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: GNL1 NM_005275.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16706026).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNL1	NM_005275.5	c.847C>T	p.Arg283Trp	missense_variant	7/12	ENST00000376621.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNL1	ENST00000376621.8	c.847C>T	p.Arg283Trp	missense_variant	7/12	1	NM_005275.5	P1
GNL1	ENST00000487166.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251376 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000170 AC: 249 AN: 1461490 Hom.: 0 Cov.: 31 AF XY: 0.000173 AC XY: 126 AN XY: 727062

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000200

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74304

Gnomad4 AFR AF: 0.0000241

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: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.00

EpiControl AF: 0.000119

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

Jan 26, 2022

The c.847C>T (p.R283W) alteration is located in exon 7 (coding exon 7) of the GNL1 gene. This alteration results from a C to T substitution at nucleotide position 847, causing the arginine (R) at amino acid position 283 to be replaced by a tryptophan (W). 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	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.73	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.17
Sift	Benign	0.11	T
Sift4G	Uncertain	0.043	D
Polyphen		0.99	D
Vest4		0.30
MVP		0.49
MPC		1.3
ClinPred		0.18	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs371929141; hg19: chr6-30520918;