8-102270176-T-C

Position:

• chr8-102270176-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015902.6(UBR5):​c.7093A>G​(p.Arg2365Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBR5 NM_015902.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

Genes affected

UBR5 (HGNC:16806): (ubiquitin protein ligase E3 component n-recognin 5) This gene encodes a progestin-induced protein, which belongs to the HECT (homology to E6-AP carboxyl terminus) family. The HECT family proteins function as E3 ubiquitin-protein ligases, targeting specific proteins for ubiquitin-mediated proteolysis. This gene is localized to chromosome 8q22 which is disrupted in a variety of cancers. This gene potentially has a role in regulation of cell proliferation or differentiation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBR5	NM_015902.6	c.7093A>G	p.Arg2365Gly	missense_variant	50/59	ENST00000520539.6	NP_056986.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBR5	ENST00000520539.6	c.7093A>G	p.Arg2365Gly	missense_variant	50/59	1	NM_015902.6	ENSP00000429084.1
UBR5	ENST00000220959.8	c.7093A>G	p.Arg2365Gly	missense_variant	50/59	1		ENSP00000220959.4
UBR5	ENST00000521922.5	c.7075A>G	p.Arg2359Gly	missense_variant	50/59	5		ENSP00000427819.1
UBR5	ENST00000518205.5	c.280A>G	p.Arg94Gly	missense_variant	3/12	5		ENSP00000428693.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 21, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.0044
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	L;L;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.18	B;.;.;B
Vest4		0.71
MutPred		0.26		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);.;.;
MVP		0.35
MPC		2.3
ClinPred		0.97	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-103282404;