Genetic Variant UBXN10:p.Arg248Trp (chr1-20191303-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_152376.5(UBXN10):c.742A>T(p.Arg248Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R248K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

UBXN10
NM_152376.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.194

Variant links:

Genes affected

UBXN10 (HGNC:26354): (UBX domain protein 10) Involved in cilium assembly. Located in cilium. Colocalizes with intraciliary transport particle B. [provided by Alliance of Genome Resources, Apr 2022]

UBXN10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a mutagenesis_site Reduced interaction with VCP. (size 0) in uniprot entity UBX10_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBXN10	NM_152376.5 link	c.742A>T	p.Arg248Trp	missense_variant	Exon 2 of 2	ENST00000375099.4	NP_689589.1	Q96LJ8
UBXN10	XM_005245742.5 link	c.742A>T	p.Arg248Trp	missense_variant	Exon 2 of 2		XP_005245799.1	Q96LJ8
UBXN10	XM_011540699.4 link	c.742A>T	p.Arg248Trp	missense_variant	Exon 2 of 2		XP_011539001.1	Q96LJ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBXN10	ENST00000375099.4 link	c.742A>T	p.Arg248Trp	missense_variant	Exon 2 of 2	1	NM_152376.5	ENSP00000364240.3		Q96LJ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251492

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135918

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:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727248

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:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.742A>T (p.R248W) alteration is located in exon 2 (coding exon 1) of the UBXN10 gene. This alteration results from a A to T substitution at nucleotide position 742, causing the arginine (R) at amino acid position 248 to be replaced by a tryptophan (W). 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

Uncertain

0.49

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

Eigen

Benign

0.13

Eigen_PC

Benign

-0.014

FATHMM_MKL

Benign

0.37

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.66

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-7.4

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.64

MutPred

0.76

Loss of disorder (P = 0.0022);

MVP

0.10

MPC

0.62

ClinPred

0.85

GERP RS

-1.2

Varity_R

0.75

gMVP

0.68

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