4-67624201-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018227.6(UBA6):​c.2765A>G​(p.Lys922Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,610,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

UBA6
NM_018227.6 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40

Publications

0 publications found
Variant links:
Genes affected
UBA6 (HGNC:25581): (ubiquitin like modifier activating enzyme 6) Modification of proteins with ubiquitin (UBB; MIM 191339) or ubiquitin-like proteins controls many signaling networks and requires a ubiquitin-activating enzyme (E1), a ubiquitin conjugating enzyme (E2), and a ubiquitin protein ligase (E3). UBE1L2 is an E1 enzyme that initiates the activation and conjugation of ubiquitin-like proteins (Jin et al., 2007 [PubMed 17597759]).[supplied by OMIM, Mar 2008]
UBA6 Gene-Disease associations (from GenCC):
  • intellectual disability
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2334812).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
UBA6NM_018227.6 linkc.2765A>G p.Lys922Arg missense_variant Exon 30 of 33 ENST00000322244.10 NP_060697.4 A0AVT1-1A1LT96
UBA6XM_017008359.3 linkc.2765A>G p.Lys922Arg missense_variant Exon 30 of 33 XP_016863848.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
UBA6ENST00000322244.10 linkc.2765A>G p.Lys922Arg missense_variant Exon 30 of 33 1 NM_018227.6 ENSP00000313454.4 A0AVT1-1
UBA6ENST00000514261.1 linkn.162+793A>G intron_variant Intron 1 of 3 5 ENSP00000425091.1 H0Y9U5

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152102
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458196
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
725368
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33338
American (AMR)
AF:
0.00
AC:
0
AN:
44102
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26022
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39490
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85586
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53316
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5726
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1110422
Other (OTH)
AF:
0.00
AC:
0
AN:
60194
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152102
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74318
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41434
American (AMR)
AF:
0.00
AC:
0
AN:
15246
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
67972
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 30, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2765A>G (p.K922R) alteration is located in exon 30 (coding exon 30) of the UBA6 gene. This alteration results from a A to G substitution at nucleotide position 2765, causing the lysine (K) at amino acid position 922 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
0.070
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
T
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.046
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.86
D
M_CAP
Benign
0.0062
T
MetaRNN
Benign
0.23
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.98
L
PhyloP100
1.4
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.8
N
REVEL
Benign
0.092
Sift
Benign
0.084
T
Sift4G
Benign
0.20
T
Polyphen
0.029
B
Vest4
0.15
MutPred
0.72
Loss of ubiquitination at K922 (P = 0.021);
MVP
0.10
MPC
0.14
ClinPred
0.65
D
GERP RS
4.7
Varity_R
0.12
gMVP
0.82
Mutation Taster
=94/6
polymorphism

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

Other links and lift over

dbSNP: rs1435681824; hg19: chr4-68489919; API