22-37688928-C-T

Variant names:

• chr22-37688928-C-T
• rs1268968646
• NM_024313.3:c.317C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024313.3(NOL12):​c.317C>T​(p.Thr106Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NOL12 NM_024313.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29

Genes affected

NOL12 (HGNC:28585): (nucleolar protein 12) Enables identical protein binding activity. Predicted to be active in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000100101 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOL12	NM_024313.3	c.317C>T	p.Thr106Ile	missense_variant	Exon 4 of 6	ENST00000359114.9	NP_077289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOL12	ENST00000359114.9	c.317C>T	p.Thr106Ile	missense_variant	Exon 4 of 6	1	NM_024313.3	ENSP00000352021.4
ENSG00000100101	ENST00000455236.4	n.296C>T		non_coding_transcript_exon_variant	Exon 4 of 13	5		ENSP00000477208.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.317C>T (p.T106I) alteration is located in exon 4 (coding exon 4) of the NOL12 gene. This alteration results from a C to T substitution at nucleotide position 317, causing the threonine (T) at amino acid position 106 to be replaced by an isoleucine (I). 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	0.68
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.77		Loss of disorder (P = 0.0524);Loss of disorder (P = 0.0524);
MVP		0.95
MPC		0.66
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.70

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: rs1268968646; hg19: chr22-38084935;