17-44207459-C-A

Position:

• chr17-44207459-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_014233.4(UBTF):​c.2164G>T​(p.Asp722Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: UBTF NM_014233.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 6.34

Genes affected

UBTF (HGNC:12511): (upstream binding transcription factor) This gene encodes a member of the HMG-box DNA-binding protein family. The encoded protein plays a critical role in ribosomal RNA transcription as a key component of the pre-initiation complex, mediating the recruitment of RNA polymerase I to rDNA promoter regions. The encoded protein may also play important roles in chromatin remodeling and pre-rRNA processing, and its activity is regulated by both phosphorylation and acetylation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Pseudogenes of this gene are located on the short arm of chromosomes 3, 11 and X and the long arm of chromosome 11. [provided by RefSeq, Aug 2011]

UBTF (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), UBTF. . Gene score misZ 4.7489 (greater than the threshold 3.09). Trascript score misZ 6.257 (greater than threshold 3.09). GenCC has associacion of gene with childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder.
• PP5: Variant 17-44207459-C-A is Pathogenic according to our data. Variant chr17-44207459-C-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 100822.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBTF	NM_014233.4	c.2164G>T	p.Asp722Tyr	missense_variant	20/21	ENST00000436088.6	NP_055048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBTF	ENST00000436088.6	c.2164G>T	p.Asp722Tyr	missense_variant	20/21	2	NM_014233.4	ENSP00000390669.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, flagged submission	literature only	Richard Lifton Laboratory, Yale University School of Medicine	-	- -
Uncertain significance, no assertion criteria provided	literature only	Richard Lifton Laboratory, Yale University School of Medicine	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	34
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	.;T;.;T;.;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	.;.;.;.;.;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	.;L;.;L;.;.;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.059	T;D;T;D;T;T;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.58
MutPred		0.25		.;Gain of phosphorylation at D722 (P = 0.0013);.;Gain of phosphorylation at D722 (P = 0.0013);.;.;Gain of phosphorylation at D722 (P = 0.0013);
MVP		0.67
MPC		0.30
ClinPred		0.91	D
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.61
gMVP		0.058

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs483352703; hg19: chr17-42284827;