rs1555582065

chr17-44212851-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 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

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

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UBTF
• PP5: Variant 17-44212851-C-T is Pathogenic according to our data. Variant chr17-44212851-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 437909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44212851-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBTF	NM_014233.4	c.628G>A	p.Glu210Lys	missense_variant	7/21	ENST00000436088.6
ATXN7L3-AS1	NR_184071.1	n.92-9611C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBTF	ENST00000436088.6	c.628G>A	p.Glu210Lys	missense_variant	7/21	2	NM_014233.4	P1
ATXN7L3-AS1	ENST00000586560.1	n.54-3240C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000437909). The variant has been previously reported as de novo in a similarly affected individual (PMID: 28777933). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Apr 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 26, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with neurodegeneration, childhood-onset, with brain atrophy (MIM# 617672). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and identified as a recurrent de novo variant in greater than ten individuals in the literature (PMID: 29300972, PMID: 28777933). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Patient fibroblasts showed increased expression of pre-rRNA and 18S rRNA, as well as nucleolar abnormalities (PMID: 29300972). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 18, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 very strong -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 16, 2018	This variant is interpreted as a Likely Pathogenic, for Neurodegeneration, childhood-onset, with brain atrophy, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:28777933). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:28777933). -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 27, 2020	The heterozygous p.Glu210Lys variant in UBTF was identified by our study in 2 unrelated individuals with childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder. Trio exome or genome analysis showed this variant to be de novo. This variant was found to be de novo in an additional individual with confirmed paternity and maternity and neurodegeneration in childhood (PMID: 30517966). This variant is assumed de novo in at least 11 additional individuals, 10 with neurodegeneration in childhood and 1 with either intellectual disability or developmental delay, but maternity and paternity have not been confirmed (PMID: 28191890, 29300972, 28777933). This variant was absent from large population studies. Additionally, this variant has also been reported as pathogenic and likely pathogenic by multiple submitters in ClinVar (Variation ID: 437909). Animal models in drosophilia and mice have shown that this variant may cause childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder (PMID: 29300972). Furthermore, in vitro functional studies provide some evidence that the p.Glu210Lys variant may impact protein function (PMID: 28777933, 29300972). However, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder in an autosomal dominant manner based on multiple de novo reports in affected individuals and functional studies. ACMG/AMP Criteria applied: PM6_Strong, PS2, PM2, PS3_Moderate, PS4_moderate (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 16, 2020	The UBTF c.628G>A (p.Glu210Lys) variant is a missense variant that has been reported in 14 unrelated individuals with childhood-onset neurodegeneration (Edvardson et al. 2017; Toro et al. 2018; Sedláčková et al. 2019; Ikeda et al. 2020; Bastos et al. 2020). In all cases, the variant occurred de novo. The p.Glu210Lys variant is absent from the Genome Aggregation Database in a region of good sequencing coverage, indicating it is rare. Studies of patient fibroblasts have suggested a gain-of-function effect of the variant, demonstrating increased expression of pre-rRNA and 18S rRNA, altered expression levels of downstream gene targets, increased double-strand DNA breaks, disrupted cell cycle progression and increased apoptosis, and at least a trend toward fewer nucleoli (Edvardson et al. 2017, Toro et al. 2018). Expression of the variant in Drosophila also resulted in embryonic lethality (Toro et al. 2018). Based on the collective evidence, the p.Glu210Lys variant is classified as pathogenic for childhood-onset neurodegeneration with brain atrophy. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 07, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Infantile or childhood onset neurodegenerative disease, global developmental delay, and intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health

Sep 11, 2017

We have 3 patients with similar clinical phenotype, not otherwise associated with other genes, shown to harbor this particular variant that was found by exome sequencing. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2017

- -

UBTF E210K Neuroregression Syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing;in vitro

Mark LeDoux Lab, University of Tennessee Health Science Center

Sep 02, 2017

Patient fibroblasts showed normal levels of UBTF transcript, increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA breaks, defective cell-cycle progression, and apoptosis. Expression of mutant human UBTF NM_014233.3:c.628G>A cDNA in Drosophila neurons was lethal. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PP5_very strong;PM1_moderate;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting -

Rare syndromic intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2020

The p.Glu210Lys variant in UBTF has been reported as a de novo occurrence, with maternity and paternity confirmed, in at least 10 individuals with clinical features of neurodegeneration in childhood (Edvardson et al 2017; Kosmicki et al 2017; Sedlackova et al 2018; Toro et al 2018; Bastos et al 2020). This variant has been reported in ClinVar (Variation ID: 437909) and was absent from large population studies. In vitro functional studies provide evidence that the p.Glu210Lys variant impacts protein function (PMID: 28777933, 29300972). However, these types of assays may not accurately represent biological function. Additionally, computational prediction tools and conservation analysis suggest that the p.Glu210Lys variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for neurodegeneration in childhood in an autosomal dominant manner based upon de novo inheritance in multiple cases and absence from controls. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4, PM2, PS3_Moderate, PP3. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 08, 2023

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23020937, 29300972, 28777933, 30517966, 31931739, 28191890, 29447355, 33084218, 33026538, 33726816, 31785789, 33101984) -

UBTF-related disorder Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as pathogenic and reported on 09/21/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;M;.;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.72	N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.16	T;D;T;T;D;T;T;D
Sift4G	Uncertain	0.060	T;D;D;T;D;T;T;D
Polyphen		0.57	P;D;D;P;D;P;P;D
Vest4		0.63
MutPred		0.59		Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);Gain of MoRF binding (P = 0.008);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

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: rs1555582065; hg19: chr17-42290219;