17-44207246-T-G

Variant names:

• chr17-44207246-T-G
• rs776223010
• NM_014233.4:c.2291A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014233.4(UBTF):​c.2291A>C​(p.Asn764Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,374 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 (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: UBTF NM_014233.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

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]

ATXN7L3-AS1 (HGNC:55298): (ATXN7L3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2675457).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014233.4. 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
	UBTF	NM_014233.4	MANE Select	c.2291A>C	p.Asn764Thr	missense	Exon 21 of 21	NP_055048.1	P17480-1
	UBTF	NM_001076683.2		c.2180A>C	p.Asn727Thr	missense	Exon 20 of 20	NP_001070151.1	P17480-2
	UBTF	NM_001076684.3		c.2180A>C	p.Asn727Thr	missense	Exon 20 of 20	NP_001070152.1	P17480-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBTF	ENST00000436088.6	TSL:2 MANE Select	c.2291A>C	p.Asn764Thr	missense	Exon 21 of 21	ENSP00000390669.1	P17480-1
	UBTF	ENST00000529383.5	TSL:1	c.2291A>C	p.Asn764Thr	missense	Exon 20 of 20	ENSP00000435708.1	P17480-1
	UBTF	ENST00000343638.9	TSL:1	c.2180A>C	p.Asn727Thr	missense	Exon 20 of 20	ENSP00000345297.5	P17480-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249264 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461374 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726932

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111866

Other (OTH) AF: 0.0000331 AC: 2 AN: 60374

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.2	L
PhyloP100		4.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		0.21	B
Vest4		0.32
MutPred		0.25		Gain of phosphorylation at N764 (P = 0.0078)
MVP		0.41
MPC		0.25
ClinPred		0.63	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.0059
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs776223010; hg19: chr17-42284614;