chr14-93218680-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBS1_Supporting

The NM_175748.4(UBR7):ā€‹c.755A>Cā€‹(p.Lys252Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000089 ( 0 hom. )

Consequence

UBR7
NM_175748.4 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.64
Variant links:
Genes affected
UBR7 (HGNC:20344): (ubiquitin protein ligase E3 component n-recognin 7) This gene encodes a UBR box-containing protein that belongs to the E3 ubiquitin ligase family. The protein also contains a plant homeodomain (PHD) in the C-terminus. In mammals, the encoded protein recognizes N-degrons, the destabilizing N-terminal residues of short-lived proteins, which results in ubiquitinylation, and proteolysis via the proteasome. [provided by RefSeq, Jul 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1
In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) (size 0) in uniprot entity UBR7_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.072392106).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000263 (4/152204) while in subpopulation EAS AF= 0.00077 (4/5196). AF 95% confidence interval is 0.000263. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
UBR7NM_175748.4 linkuse as main transcriptc.755A>C p.Lys252Thr missense_variant 7/11 ENST00000013070.11
UBR7NR_038150.2 linkuse as main transcriptn.657A>C non_coding_transcript_exon_variant 6/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
UBR7ENST00000013070.11 linkuse as main transcriptc.755A>C p.Lys252Thr missense_variant 7/111 NM_175748.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152204
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:
0.000770
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251426
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000435
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461882
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000629
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000770
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000494
AC:
6

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 GeneticsDec 28, 2023The c.755A>C (p.K252T) alteration is located in exon 7 (coding exon 7) of the UBR7 gene. This alteration results from a A to C substitution at nucleotide position 755, causing the lysine (K) at amino acid position 252 to be replaced by a threonine (T). 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
0.063
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.017
T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.22
FATHMM_MKL
Benign
0.75
D
M_CAP
Benign
0.065
D
MetaRNN
Benign
0.072
T
MetaSVM
Benign
-0.72
T
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.16
Sift
Benign
0.099
T
Sift4G
Benign
0.40
T
Polyphen
0.0020
B
Vest4
0.20
MutPred
0.34
Loss of ubiquitination at K252 (P = 8e-04);
MVP
0.90
MPC
0.81
ClinPred
0.18
T
GERP RS
4.7
Varity_R
0.086
gMVP
0.30

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: rs758341511; hg19: chr14-93685026; API