9-83666364-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_013438.5(UBQLN1):ā€‹c.1318A>Gā€‹(p.Thr440Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,588 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000096 ( 0 hom. )

Consequence

UBQLN1
NM_013438.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75
Variant links:
Genes affected
UBQLN1 (HGNC:12508): (ubiquilin 1) This gene encodes an ubiquitin-like protein (ubiquilin) that shares a high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain an N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases, and thus are thought to functionally link the ubiquitination machinery to the proteasome to affect in vivo protein degradation. This ubiquilin has also been shown to modulate accumulation of presenilin proteins, and it is found in lesions associated with Alzheimer's and Parkinson's disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17135587).
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
UBQLN1NM_013438.5 linkuse as main transcriptc.1318A>G p.Thr440Ala missense_variant 8/11 ENST00000376395.9 NP_038466.2 Q9UMX0-1
UBQLN1NM_053067.3 linkuse as main transcriptc.1249-1219A>G intron_variant NP_444295.1 Q9UMX0-2A0A024R258

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
UBQLN1ENST00000376395.9 linkuse as main transcriptc.1318A>G p.Thr440Ala missense_variant 8/111 NM_013438.5 ENSP00000365576.4 Q9UMX0-1
UBQLN1ENST00000257468.11 linkuse as main transcriptc.1249-1219A>G intron_variant 1 ENSP00000257468.7 Q9UMX0-2
UBQLN1ENST00000533705.5 linkuse as main transcriptn.3787A>G non_coding_transcript_exon_variant 6/91
UBQLN1ENST00000526134.1 linkuse as main transcriptc.136A>G p.Thr46Ala missense_variant 2/53 ENSP00000436912.1 H0YEZ9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251178
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135750
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461588
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
10
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 13, 2023The c.1318A>G (p.T440A) alteration is located in exon 8 (coding exon 8) of the UBQLN1 gene. This alteration results from a A to G substitution at nucleotide position 1318, causing the threonine (T) at amino acid position 440 to be replaced by an alanine (A). 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
0.071
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
22
DANN
Benign
0.86
DEOGEN2
Benign
0.14
T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.0059
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.34
T
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.17
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.53
N
REVEL
Benign
0.092
Sift
Benign
0.58
T
Sift4G
Benign
1.0
T
Polyphen
0.0010
B
Vest4
0.56
MutPred
0.095
Gain of glycosylation at P439 (P = 0.3103);
MVP
0.62
MPC
0.34
ClinPred
0.056
T
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.041
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs760831264; hg19: chr9-86281279; API