1-19076890-T-C

Position:

• chr1-19076890-T-C

Variant summary

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

The NM_020765.3(UBR4):​c.15337A>G​(p.Ser5113Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,411,722 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 7.67

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 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
UBR4	NM_020765.3	c.15337A>G	p.Ser5113Gly	missense_variant	105/106	ENST00000375254.8	NP_065816.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBR4	ENST00000375254.8	c.15337A>G	p.Ser5113Gly	missense_variant	105/106	1	NM_020765.3	ENSP00000364403	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1411722 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698528

Gnomad4 AFR exome AF: 0.00

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Nov 09, 2021

The c.15337A>G (p.S5113G) alteration is located in exon 105 (coding exon 105) of the UBR4 gene. This alteration results from a A to G substitution at nucleotide position 15337, causing the serine (S) at amino acid position 5113 to be replaced by a glycine (G). 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	0.084
BayesDel_addAF	Benign	0.0099	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.25	T;T;T
Sift4G	Pathogenic	0.0	.;D;T
Polyphen		0.96	D;.;.
Vest4		0.69
MutPred		0.20		Loss of glycosylation at S5113 (P = 0.0447);.;.;
MVP		0.068
MPC		0.63
ClinPred		0.83	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2075995111; hg19: chr1-19403384;