1-19081374-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_020765.3(UBR4):c.15208G>A(p.Ala5070Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UBR4 NM_020765.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

Genes affected

UBR4 (HGNC:30313): (ubiquitin protein ligase E3 component n-recognin 4) The protein encoded by this gene is an E3 ubiquitin-protein ligase that interacts with the retinoblastoma-associated protein in the nucleus and with calcium-bound calmodulin in the cytoplasm. The encoded protein appears to be a cytoskeletal component in the cytoplasm and part of the chromatin scaffold in the nucleus. In addition, this protein is a target of the human papillomavirus type 16 E7 oncoprotein. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, UBR4
• BP4: Computational evidence support a benign effect (MetaRNN=0.14047775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBR4	NM_020765.3	c.15208G>A	p.Ala5070Thr	missense_variant	103/106	ENST00000375254.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBR4	ENST00000375254.8	c.15208G>A	p.Ala5070Thr	missense_variant	103/106	1	NM_020765.3	P1
UBR4	ENST00000375224.1	c.2329G>A	p.Ala777Thr	missense_variant	18/21	2
UBR4	ENST00000375225.7	c.433G>A	p.Ala145Thr	missense_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456488 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724062

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2023

The c.15208G>A (p.A5070T) alteration is located in exon 103 (coding exon 103) of the UBR4 gene. This alteration results from a G to A substitution at nucleotide position 15208, causing the alanine (A) at amino acid position 5070 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	0.071
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.064
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	0.85	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.055
Sift	Benign	0.25	T;T;T
Polyphen		0.037	B;.;.
Vest4		0.27
MutPred		0.29		Loss of helix (P = 0.0444);.;.;
MVP		0.043
MPC		0.17
ClinPred		0.55	D
GERP RS		5.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.069
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-19407868;