3-49808027-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003335.3(UBA7):​c.2516G>A​(p.Arg839His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 1,613,996 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. R839P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

UBA7
NM_003335.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.633
Variant links:
Genes affected
UBA7 (HGNC:12471): (ubiquitin like modifier activating enzyme 7) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E1 ubiquitin-activating enzyme family. The encoded enzyme is a retinoid target that triggers promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARalpha) degradation and apoptosis in acute promyelocytic leukemia, where it is involved in the conjugation of the ubiquitin-like interferon-stimulated gene 15 protein. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.060789347).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
UBA7NM_003335.3 linkc.2516G>A p.Arg839His missense_variant Exon 20 of 24 ENST00000333486.4 NP_003326.2 P41226

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
UBA7ENST00000333486.4 linkc.2516G>A p.Arg839His missense_variant Exon 20 of 24 1 NM_003335.3 ENSP00000333266.3 P41226
UBA7ENST00000488536.1 linkn.*15G>A downstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.000335
AC:
51
AN:
152248
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000723
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:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000691
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000291
AC:
73
AN:
250752
Hom.:
0
AF XY:
0.000302
AC XY:
41
AN XY:
135614
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000627
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000369
AC:
540
AN:
1461748
Hom.:
1
Cov.:
31
AF XY:
0.000355
AC XY:
258
AN XY:
727174
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000468
Gnomad4 OTH exome
AF:
0.000132
GnomAD4 genome
AF:
0.000335
AC:
51
AN:
152248
Hom.:
0
Cov.:
33
AF XY:
0.000336
AC XY:
25
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000691
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000427
Hom.:
0
Bravo
AF:
0.000321
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000255
AC:
31
EpiCase
AF:
0.000709
EpiControl
AF:
0.000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 20, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2516G>A (p.R839H) alteration is located in exon 20 (coding exon 20) of the UBA7 gene. This alteration results from a G to A substitution at nucleotide position 2516, causing the arginine (R) at amino acid position 839 to be replaced by a histidine (H). 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
0.075
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.47
T
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.71
T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.061
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
L
PrimateAI
Benign
0.21
T
PROVEAN
Uncertain
-3.3
D
REVEL
Benign
0.079
Sift
Benign
0.083
T
Sift4G
Uncertain
0.060
T
Polyphen
0.62
P
Vest4
0.097
MVP
0.20
MPC
0.30
ClinPred
0.11
T
GERP RS
-0.67
Varity_R
0.10
gMVP
0.51

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.

Other links and lift over

dbSNP: rs118020287; hg19: chr3-49845460; API