17-44207324-T-C

Position:

• chr17-44207324-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_014233.4(UBTF):​c.2213A>G​(p.Asp738Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: UBTF NM_014233.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08

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 Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21705174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBTF	NM_014233.4	c.2213A>G	p.Asp738Gly	missense_variant	21/21	ENST00000436088.6	NP_055048.1
ATXN7L3-AS1	NR_184071.1	n.91+8394T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBTF	ENST00000436088.6	c.2213A>G	p.Asp738Gly	missense_variant	21/21	2	NM_014233.4	ENSP00000390669	P1
ATXN7L3-AS1	ENST00000586560.1	n.53+8390T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 09, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Benign	0.85
DEOGEN2	Benign	0.11	.;T;.;T;.;.;T
Eigen	Benign	-0.0061
Eigen_PC	Benign	0.021
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.79	.;.;.;.;.;T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	0.0	.;N;.;N;.;.;N
MutationTaster	Benign	0.82	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N;N;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D
Polyphen		0.030	B;B;B;B;B;B;B
Vest4		0.17
MutPred		0.19		.;Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);.;.;Loss of helix (P = 0.0376);
MVP		0.75
MPC		0.32
ClinPred		0.29	T
GERP RS		5.2
Varity_R		0.45
gMVP		0.0098

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2056307553; hg19: chr17-42284692;