Variant 9-83666364-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_013438.5(UBQLN1):c.1318A>G(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 (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

UBQLN1
NM_013438.5 missense

Scores

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]

UBQLN1 links:

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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
UBQLN1	NM_013438.5 linkuse as main transcript	c.1318A>G	p.Thr440Ala	missense_variant	8/11	ENST00000376395.9	NP_038466.2	Q9UMX0-1
UBQLN1	NM_053067.3 linkuse as main transcript	c.1249-1219A>G		intron_variant			NP_444295.1	Q9UMX0-2A0A024R258

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
UBQLN1	ENST00000376395.9 linkuse as main transcript	c.1318A>G	p.Thr440Ala	missense_variant	8/11	1	NM_013438.5	ENSP00000365576.4	Q9UMX0-1
UBQLN1	ENST00000257468.11 linkuse as main transcript	c.1249-1219A>G		intron_variant		1		ENSP00000257468.7	Q9UMX0-2
UBQLN1	ENST00000533705.5 linkuse as main transcript	n.3787A>G		non_coding_transcript_exon_variant	6/9	1
UBQLN1	ENST00000526134.1 linkuse as main transcript	c.136A>G	p.Thr46Ala	missense_variant	2/5	3		ENSP00000436912.1	H0YEZ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251178

Hom.:

AF XY:

0.0000221

AC XY:

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:

AN:

1461588

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

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.:

Alfa

AF:

0.0000868

Hom.:

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 submitter

clinical testing

Ambry Genetics

Nov 13, 2023

The 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

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.14

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.0059

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.34

M_CAP

Benign

0.0057

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.53

REVEL

Benign

0.092

Sift

Benign

0.58

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.56

MutPred

0.095

Gain of glycosylation at P439 (P = 0.3103);

MVP

0.62

MPC

0.34

ClinPred

0.056

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.

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