NM_014233.4:c.628G>A

Variant names:

• chr17-44212851-C-T
• rs1555582065
• NM_014233.4:c.628G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_014233.4(UBTF):​c.628G>A​(p.Glu210Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UBTF NM_014233.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 7.53
• Publications: 9 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44212851-C-T is Pathogenic according to our data. Variant chr17-44212851-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 437909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.628G>A	p.Glu210Lys	missense	Exon 7 of 21	NP_055048.1	P17480-1
	UBTF	NM_001076683.2		c.628G>A	p.Glu210Lys	missense	Exon 7 of 20	NP_001070151.1	P17480-2
	UBTF	NM_001076684.3		c.628G>A	p.Glu210Lys	missense	Exon 7 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.628G>A	p.Glu210Lys	missense	Exon 7 of 21	ENSP00000390669.1	P17480-1
	UBTF	ENST00000529383.5	TSL:1	c.628G>A	p.Glu210Lys	missense	Exon 6 of 20	ENSP00000435708.1	P17480-1
	UBTF	ENST00000343638.9	TSL:1	c.628G>A	p.Glu210Lys	missense	Exon 7 of 20	ENSP00000345297.5	P17480-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder (13)
1	-	-	Inborn genetic diseases (1)
1	-	-	Infantile or childhood onset neurodegenerative disease, global developmental delay, and intellectual disability (1)
1	-	-	not provided (1)
1	-	-	Rare syndromic intellectual disability (1)
1	-	-	See cases (1)
1	-	-	UBTF E210K Neuroregression Syndrome (1)
-	-	-	UBTF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.72	N
REVEL	Pathogenic	0.68
Sift	Benign	0.16	T
Sift4G	Uncertain	0.060	T
Polyphen		0.57	P
Vest4		0.63
MutPred		0.59		Gain of MoRF binding (P = 0.008)
MVP		0.68
MPC		2.6
ClinPred		0.91	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.41
gMVP		0.95
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs1555582065; hg19: chr17-42290219;