17-67719906-G-C

Variant names:

• chr17-67719906-G-C
• rs781745657
• NM_015462.5:c.256G>C

Variant summary

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

The NM_015462.5(NOL11):​c.256G>C​(p.Val86Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000706 in 1,417,056 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V86I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NOL11 NM_015462.5 missense, splice_region
• Scores: Splicing: ADA: 0.9188
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.09
• Publications: 0 publications found

Genes affected

NOL11 (HGNC:24557): (nucleolar protein 11) Enables RNA binding activity. Involved in maturation of SSU-rRNA and positive regulation of transcription of nucleolar large rRNA by RNA polymerase I. Located in nucleolus. Part of t-UTP complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000288109 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015462.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOL11	NM_015462.5	MANE Select	c.256G>C	p.Val86Leu	missense splice_region	Exon 3 of 18	NP_056277.2
	NOL11	NM_001303272.2		c.-233G>C		splice_region	Exon 3 of 17	NP_001290201.1
	NOL11	NM_001303272.2		c.-233G>C		5_prime_UTR	Exon 3 of 17	NP_001290201.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOL11	ENST00000253247.9	TSL:1 MANE Select	c.256G>C	p.Val86Leu	missense splice_region	Exon 3 of 18	ENSP00000253247.4	Q9H8H0-1
	NOL11	ENST00000918421.1		c.406G>C	p.Val136Leu	missense splice_region	Exon 3 of 18	ENSP00000588480.1
	NOL11	ENST00000918420.1		c.256G>C	p.Val86Leu	missense splice_region	Exon 3 of 18	ENSP00000588479.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1417056 Hom.: 0 Cov.: 29 AF XY: 0.00000142 AC XY: 1 AN XY: 705944

African (AFR) AF: 0.00 AC: 0 AN: 31966

American (AMR) AF: 0.00 AC: 0 AN: 40040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25536

East Asian (EAS) AF: 0.00 AC: 0 AN: 38996

South Asian (SAS) AF: 0.00 AC: 0 AN: 80802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4022

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084192

Other (OTH) AF: 0.00 AC: 0 AN: 58626

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.034	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.014	D
Polyphen		0.14	B
Vest4		0.49
MutPred		0.76		Loss of methylation at K85 (P = 0.0526)
MVP		0.53
MPC		0.21
ClinPred		0.95	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.48
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.75
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.38		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781745657; hg19: chr17-65716022;