4-2939339-C-T

Variant names:

• chr4-2939339-C-T
• rs145832505
• NM_001291978.2:c.2323G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001291978.2(NOP14):​c.2323G>A​(p.Glu775Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000196 in 1,614,016 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E775Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: NOP14 NM_001291978.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.52

Genes affected

NOP14 (HGNC:16821): (NOP14 nucleolar protein) This gene encodes a protein that plays a role in pre-18s rRNA processing and small ribosomal subunit assembly. The encoded protein may be involved in the regulation of pancreatic cancer cell proliferation and migration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

NOP14-AS1 (HGNC:20205): (NOP14 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30424243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOP14	NM_001291978.2	c.2323G>A	p.Glu775Lys	missense_variant	Exon 17 of 18	ENST00000416614.7	NP_001278907.1
NOP14	NM_003703.3	c.2323G>A	p.Glu775Lys	missense_variant	Exon 17 of 19		NP_003694.1
NOP14	NM_001291979.2	c.2306+200G>A		intron_variant	Intron 16 of 16		NP_001278908.1
NOP14-AS1	NR_015453.2	n.2697+547C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOP14	ENST00000416614.7	c.2323G>A	p.Glu775Lys	missense_variant	Exon 17 of 18	1	NM_001291978.2	ENSP00000405068.2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000263 AC: 66 AN: 251280 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135818

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000202 AC: 295 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.000216 AC XY: 157 AN XY: 727134

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00210

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74466

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000383 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2323G>A (p.E775K) alteration is located in exon 17 (coding exon 17) of the NOP14 gene. This alteration results from a G to A substitution at nucleotide position 2323, causing the glutamic acid (E) at amino acid position 775 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	Pathogenic	0.66
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.21
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.16	T;T
Polyphen		1.0	D;D
Vest4		0.64
MVP		0.65
MPC		0.44
ClinPred		0.40	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145832505; hg19: chr4-2941066; COSMIC: COSV58624248; COSMIC: COSV58624248;