17-44207480-C-T

Position:

• chr17-44207480-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_014233.4(UBTF):​c.2143G>A​(p.Glu715Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UBTF NM_014233.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBTF	NM_014233.4	c.2143G>A	p.Glu715Lys	missense_variant	20/21	ENST00000436088.6	NP_055048.1
ATXN7L3-AS1	NR_184071.1	n.91+8550C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBTF	ENST00000436088.6	c.2143G>A	p.Glu715Lys	missense_variant	20/21	2	NM_014233.4	ENSP00000390669	P1
ATXN7L3-AS1	ENST00000586560.1	n.53+8546C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.2143G>A (p.E715K) alteration is located in exon 20 (coding exon 19) of the UBTF gene. This alteration results from a G to A substitution at nucleotide position 2143, causing the glutamic acid (E) at amino acid position 715 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	.;T;.;T;.;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	.;.;.;.;.;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	0.97	.;L;.;L;.;.;L
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.61	N;N;N;N;N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.051	T;D;T;D;T;T;D
Sift4G	Uncertain	0.033	D;T;D;T;D;D;T
Polyphen		0.98	D;D;D;D;D;D;D
Vest4		0.51
MutPred		0.18		.;Gain of ubiquitination at E715 (P = 0.0155);.;Gain of ubiquitination at E715 (P = 0.0155);.;.;Gain of ubiquitination at E715 (P = 0.0155);
MVP		0.72
MPC		0.28
ClinPred		0.87	D
GERP RS		5.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.51
gMVP		0.036

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: rs1054670510; hg19: chr17-42284848; COSMIC: COSV105137862; COSMIC: COSV105137862;