Genetic Variant UBOX5:p.His335Arg (chr20-3121635-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_014948.4(UBOX5):c.1004A>G(p.His335Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,459,508 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000032 ( 1 hom. )

Consequence

UBOX5
NM_014948.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.91

Variant links:

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 links:

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

UBOX5-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35113174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBOX5	NM_014948.4 link	c.1004A>G	p.His335Arg	missense_variant	Exon 3 of 5	ENST00000217173.7	NP_055763.1	O94941-1
UBOX5	NM_001267584.2 link	c.1004A>G	p.His335Arg	missense_variant	Exon 3 of 5		NP_001254513.1
UBOX5	NM_199415.3 link	c.1004A>G	p.His335Arg	missense_variant	Exon 3 of 4		NP_955447.1	O94941-2
UBOX5-AS1	NR_038395.1 link	n.1308+9883T>C		intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
UBOX5	ENST00000217173.7 link	c.1004A>G	p.His335Arg	missense_variant	Exon 3 of 5	1	NM_014948.4	ENSP00000217173.2	O94941-1
UBOX5	ENST00000348031.6 link	c.1004A>G	p.His335Arg	missense_variant	Exon 3 of 4	1		ENSP00000311726.3	O94941-2
UBOX5-AS1	ENST00000446537.5 link	n.1306+9883T>C		intron_variant	Intron 5 of 6	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000650

AC:

AN:

246172

Hom.:

AF XY:

0.0000677

AC XY:

AN XY:

133028

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000466

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1459508

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

725860

show subpopulations

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:

0.000501

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.000104

Hom.:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1004A>G (p.H335R) alteration is located in exon 3 (coding exon 2) of the UBOX5 gene. This alteration results from a A to G substitution at nucleotide position 1004, causing the histidine (H) at amino acid position 335 to be replaced by an arginine (R). 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

0.16

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.0099

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.17

N;N

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.24

Sift

Benign

0.032

D;D

Sift4G

Uncertain

0.037

D;D

Polyphen

1.0

D;.

Vest4

0.59

MutPred

0.63

Loss of catalytic residue at H335 (P = 0.0645);Loss of catalytic residue at H335 (P = 0.0645);

MVP

0.58

MPC

0.64

ClinPred

0.21

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.076

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over