15-42945374-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_174916.3(UBR1):c.5205A>G(p.Gln1735=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,614,116 control chromosomes in the GnomAD database, including 1,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (396 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1553 hom.)
• Consequence: UBR1 NM_174916.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.379

Genes affected

UBR1 (HGNC:16808): (ubiquitin protein ligase E3 component n-recognin 1) The N-end rule pathway is one proteolytic pathway of the ubiquitin system. The recognition component of this pathway, encoded by this gene, binds to a destabilizing N-terminal residue of a substrate protein and participates in the formation of a substrate-linked multiubiquitin chain. This leads to the eventual degradation of the substrate protein. The protein described in this record has a RING-type zinc finger and a UBR-type zinc finger. Mutations in this gene have been associated with Johanson-Blizzard syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-42945374-T-C is Benign according to our data. Variant chr15-42945374-T-C is described in ClinVar as [Benign]. Clinvar id is 262897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.379 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBR1	NM_174916.3	c.5205A>G	p.Gln1735=	synonymous_variant	47/47	ENST00000290650.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBR1	ENST00000290650.9	c.5205A>G	p.Gln1735=	synonymous_variant	47/47	1	NM_174916.3	P1
UBR1	ENST00000562173.1	n.410A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 9227 AN: 152142 Hom.: 394 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0515

Gnomad ASJ AF: 0.0858

Gnomad EAS AF: 0.0613

Gnomad SAS AF: 0.0823

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0545

GnomAD3 exomes AF: 0.0476 AC: 11960 AN: 251446 Hom.: 415 AF XY: 0.0481 AC XY: 6535 AN XY: 135904

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.0371

Gnomad ASJ exome AF: 0.0839

Gnomad EAS exome AF: 0.0589

Gnomad SAS exome AF: 0.0795

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0455

GnomAD4 exome AF: 0.0386 AC: 56396 AN: 1461856 Hom.: 1553 Cov.: 31 AF XY: 0.0399 AC XY: 29006 AN XY: 727226

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.0374

Gnomad4 ASJ exome AF: 0.0822

Gnomad4 EAS exome AF: 0.0840

Gnomad4 SAS exome AF: 0.0790

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.0306

Gnomad4 OTH exome AF: 0.0488

GnomAD4 genome AF: 0.0607 AC: 9239 AN: 152260 Hom.: 396 Cov.: 32 AF XY: 0.0610 AC XY: 4539 AN XY: 74440

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0515

Gnomad4 ASJ AF: 0.0858

Gnomad4 EAS AF: 0.0615

Gnomad4 SAS AF: 0.0824

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.0307

Gnomad4 OTH AF: 0.0535

Alfa AF: 0.0440 Hom.: 286

Bravo AF: 0.0642

Asia WGS AF: 0.0830 AC: 288 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	6.1
Dann	Benign	0.54

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

LitVar

Other links and lift over

dbSNP: rs16957277; hg19: chr15-43237572; COSMIC: COSV51930057;