chr6-42659696-G-A

Position:

• chr6-42659696-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001363705.2(UBR2):​c.3283G>A​(p.Ala1095Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,610,270 control chromosomes in the GnomAD database, including 128,438 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1095P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.42 (13722 hom., cov: 30)
  • Exomes 𝑓: 0.39 (114716 hom.)
• Consequence: UBR2 NM_001363705.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

Genes affected

UBR2 (HGNC:21289): (ubiquitin protein ligase E3 component n-recognin 2) Enables leucine binding activity. Involved in cellular response to leucine and negative regulation of TOR signaling. Predicted to be located in cytosol. Predicted to be part of ubiquitin ligase complex. Predicted to be active in cytoplasm. Predicted to colocalize with chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7169118E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBR2	NM_001363705.2	c.3283G>A	p.Ala1095Thr	missense_variant	30/47	ENST00000372901.2	NP_001350634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBR2	ENST00000372901.2	c.3283G>A	p.Ala1095Thr	missense_variant	30/47	5	NM_001363705.2	ENSP00000361992	P3
UBR2	ENST00000372899.6	c.3283G>A	p.Ala1095Thr	missense_variant	30/47	1		ENSP00000361990	A1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64312 AN: 151512 Hom.: 13704 Cov.: 30

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.438

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.424

GnomAD3 exomes AF: 0.403 AC: 100849 AN: 250118 Hom.: 20413 AF XY: 0.400 AC XY: 54071 AN XY: 135144

Gnomad AFR exome AF: 0.489

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.441

Gnomad EAS exome AF: 0.404

Gnomad SAS exome AF: 0.389

Gnomad FIN exome AF: 0.427

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.394 AC: 575271 AN: 1458640 Hom.: 114716 Cov.: 46 AF XY: 0.394 AC XY: 285818 AN XY: 725742

Gnomad4 AFR exome AF: 0.486

Gnomad4 AMR exome AF: 0.391

Gnomad4 ASJ exome AF: 0.443

Gnomad4 EAS exome AF: 0.450

Gnomad4 SAS exome AF: 0.383

Gnomad4 FIN exome AF: 0.431

Gnomad4 NFE exome AF: 0.388

Gnomad4 OTH exome AF: 0.397

GnomAD4 genome AF: 0.424 AC: 64359 AN: 151630 Hom.: 13722 Cov.: 30 AF XY: 0.424 AC XY: 31423 AN XY: 74044

Gnomad4 AFR AF: 0.485

Gnomad4 AMR AF: 0.405

Gnomad4 ASJ AF: 0.438

Gnomad4 EAS AF: 0.423

Gnomad4 SAS AF: 0.394

Gnomad4 FIN AF: 0.435

Gnomad4 NFE AF: 0.394

Gnomad4 OTH AF: 0.420

Alfa AF: 0.396 Hom.: 30341

Bravo AF: 0.425

TwinsUK AF: 0.407 AC: 1509

ALSPAC AF: 0.387 AC: 1490

ESP6500AA AF: 0.482 AC: 2124

ESP6500EA AF: 0.392 AC: 3370

ExAC AF: 0.404 AC: 49037

Asia WGS AF: 0.414 AC: 1436 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.7
DANN	Benign	0.89
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.00017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.054
Sift	Benign	0.40	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.091	B;B
Vest4		0.016
MPC		0.39
ClinPred		0.0019	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.012
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs6917033; hg19: chr6-42627434; COSMIC: COSV65750383; COSMIC: COSV65750383;