20-3115331-G-T

Position:

• chr20-3115331-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014948.4(UBOX5):​c.1391C>A​(p.Thr464Asn) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBOX5 NM_014948.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

Genes affected

UBOX5 (HGNC:17777): (U-box domain containing 5) This gene encodes a U-box domain containing protein. The encoded protein interacts with E2 enzymes and may play a role in the ubiquitination pathway. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

UBOX5-AS1 (HGNC:44111): (UBOX5 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08837956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBOX5	NM_014948.4	c.1391C>A	p.Thr464Asn	missense_variant	4/5	ENST00000217173.7	NP_055763.1
UBOX5-AS1	NR_038395.1	n.1308+3579G>T		intron_variant, non_coding_transcript_variant
UBOX5	NM_001267584.2	c.1391C>A	p.Thr464Asn	missense_variant	4/5		NP_001254513.1
UBOX5	NM_199415.3	c.1256-5017C>A		intron_variant			NP_955447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBOX5	ENST00000217173.7	c.1391C>A	p.Thr464Asn	missense_variant	4/5	1	NM_014948.4	ENSP00000217173	P1
UBOX5	ENST00000348031.6	c.1256-5017C>A		intron_variant		1		ENSP00000311726
UBOX5-AS1	ENST00000446537.5	n.1306+3579G>T		intron_variant, non_coding_transcript_variant		2
UBOX5-AS1	ENST00000454019.1	n.191-1158G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.1391C>A (p.T464N) alteration is located in exon 4 (coding exon 3) of the UBOX5 gene. This alteration results from a C to A substitution at nucleotide position 1391, causing the threonine (T) at amino acid position 464 to be replaced by an asparagine (N). 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	Benign	0.082
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.11
Sift	Benign	0.044	D
Sift4G	Benign	0.079	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.17		Gain of loop (P = 0.0079);
MVP		0.44
MPC		0.31
ClinPred		0.15	T
GERP RS		4.0
Varity_R		0.14
gMVP		0.21

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: rs1372502364; hg19: chr20-3095977;