1-19078075-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020765.3(UBR4):c.15234-9C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,613,540 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (26 hom.)
• Consequence: UBR4 NM_020765.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003317
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.250

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-19078075-G-C is Benign according to our data. Variant chr1-19078075-G-C is described in ClinVar as [Benign]. Clinvar id is 777888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00707 (1077/152234) while in subpopulation AFR AF= 0.0231 (961/41544). AF 95% confidence interval is 0.0219. There are 18 homozygotes in gnomad4. There are 536 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1076 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBR4	NM_020765.3	c.15234-9C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375254.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBR4	ENST00000375254.8	c.15234-9C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_020765.3	P1
UBR4	ENST00000375224.1	c.2355-9C>G		splice_polypyrimidine_tract_variant, intron_variant		2
UBR4	ENST00000375225.7	c.459-9C>G		splice_polypyrimidine_tract_variant, intron_variant		2
UBR4	ENST00000459947.5	n.3232C>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1076 AN: 152116 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00202 AC: 507 AN: 250516 Hom.: 8 AF XY: 0.00176 AC XY: 239 AN XY: 135426

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000361

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000964 AC: 1408 AN: 1461306 Hom.: 26 Cov.: 31 AF XY: 0.000930 AC XY: 676 AN XY: 726912

Gnomad4 AFR exome AF: 0.0283

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000149

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00707 AC: 1077 AN: 152234 Hom.: 18 Cov.: 32 AF XY: 0.00720 AC XY: 536 AN XY: 74434

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00212 Hom.: 2

Bravo AF: 0.00838

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

UBR4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	13
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.042
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: rs185542873; hg19: chr1-19404569;