2-169872270-A-T

Variant names:

• chr2-169872270-A-T
• rs1257182846
• NM_172070.4:c.580A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_172070.4(UBR3):​c.580A>T​(p.Asn194Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000724 in 1,381,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N194S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: UBR3 NM_172070.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.86
• Publications: 0 publications found

Genes affected

UBR3 (HGNC:30467): (ubiquitin protein ligase E3 component n-recognin 3) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in several processes, including cellular protein metabolic process; sensory perception of smell; and suckling behavior. Predicted to act upstream of or within in utero embryonic development and olfactory behavior. Predicted to be integral component of membrane. Predicted to be part of ubiquitin ligase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37985414).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172070.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBR3	NM_172070.4	MANE Select	c.580A>T	p.Asn194Tyr	missense	Exon 2 of 39	NP_742067.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBR3	ENST00000272793.11	TSL:5 MANE Select	c.580A>T	p.Asn194Tyr	missense	Exon 2 of 39	ENSP00000272793.5	Q6ZT12-1
	UBR3	ENST00000949146.1		c.580A>T	p.Asn194Tyr	missense	Exon 2 of 40	ENSP00000619205.1
	UBR3	ENST00000949147.1		c.580A>T	p.Asn194Tyr	missense	Exon 2 of 39	ENSP00000619206.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1381960 Hom.: 0 Cov.: 28 AF XY: 0.00000147 AC XY: 1 AN XY: 680802

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000322 AC: 1 AN: 31096

American (AMR) AF: 0.00 AC: 0 AN: 32964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24914

East Asian (EAS) AF: 0.00 AC: 0 AN: 35136

South Asian (SAS) AF: 0.00 AC: 0 AN: 74112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071896

Other (OTH) AF: 0.00 AC: 0 AN: 57438

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.18
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.026	D
Polyphen		0.89	P
Vest4		0.53
MutPred		0.41		Loss of disorder (P = 0.0405)
MVP		0.12
MPC		0.93
ClinPred		0.60	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.48
Mutation Taster		=83/17	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

Other links and lift over

dbSNP: rs1257182846; hg19: chr2-170728780;