14-24300075-C-T

Variant names:

• chr14-24300075-C-T
• NM_174913.3:c.121C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_174913.3(NOP9):​c.121C>T​(p.Pro41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOP9 NM_174913.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.918

Genes affected

NOP9 (HGNC:19826): (NOP9 nucleolar protein) Enables RNA binding activity. Predicted to be involved in ribosome biogenesis. Predicted to be part of 90S preribosome and preribosome, small subunit precursor. Predicted to be active in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049773574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOP9	NM_174913.3	c.121C>T	p.Pro41Ser	missense_variant	Exon 1 of 10	ENST00000267425.8	NP_777573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOP9	ENST00000267425.8	c.121C>T	p.Pro41Ser	missense_variant	Exon 1 of 10	1	NM_174913.3	ENSP00000267425.3
NOP9	ENST00000396802.7	c.121C>T	p.Pro41Ser	missense_variant	Exon 1 of 10	5		ENSP00000380020.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460488 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726508

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.121C>T (p.P41S) alteration is located in exon 1 (coding exon 1) of the NOP9 gene. This alteration results from a C to T substitution at nucleotide position 121, causing the proline (P) at amino acid position 41 to be replaced by a serine (S). 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	0.076
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.0095	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.052	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.14	N;N
REVEL	Benign	0.012
Sift	Benign	0.67	T;T
Sift4G	Benign	0.84	T;T
Polyphen		0.0	B;.
Vest4		0.20
MutPred		0.34		Loss of catalytic residue at P41 (P = 0.0011);Loss of catalytic residue at P41 (P = 0.0011);
MVP		0.12
MPC		0.24
ClinPred		0.032	T
GERP RS		1.3
Varity_R		0.13
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24769281; COSMIC: COSV55385968; COSMIC: COSV55385968;