rs16957277

Variant names:

• chr15-42945374-T-C
• rs16957277
• NM_174916.3:c.5205A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_174916.3(UBR1):​c.5205A>G​(p.Gln1735Gln) 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:4
• Conservation: PhyloP100: 0.379
• Publications: 11 publications found

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]

UBR1 Gene-Disease associations (from GenCC):

• Johanson-Blizzard syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174916.3. 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
	UBR1	NM_174916.3	MANE Select	c.5205A>G	p.Gln1735Gln	synonymous	Exon 47 of 47	NP_777576.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBR1	ENST00000290650.9	TSL:1 MANE Select	c.5205A>G	p.Gln1735Gln	synonymous	Exon 47 of 47	ENSP00000290650.4
	UBR1	ENST00000914218.1		c.5277A>G	p.Gln1759Gln	synonymous	Exon 48 of 48	ENSP00000584277.1
	UBR1	ENST00000914217.1		c.5181A>G	p.Gln1727Gln	synonymous	Exon 47 of 47	ENSP00000584276.1

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

GnomAD2 exomes AF: 0.0476 AC: 11960 AN: 251446 AF XY: 0.0481

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 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

African (AFR) AF: 0.124 AC: 4159 AN: 33480

American (AMR) AF: 0.0374 AC: 1671 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0822 AC: 2148 AN: 26134

East Asian (EAS) AF: 0.0840 AC: 3335 AN: 39698

South Asian (SAS) AF: 0.0790 AC: 6813 AN: 86258

European-Finnish (FIN) AF: 0.0151 AC: 807 AN: 53416

Middle Eastern (MID) AF: 0.0827 AC: 477 AN: 5768

European-Non Finnish (NFE) AF: 0.0306 AC: 34038 AN: 1111988

Other (OTH) AF: 0.0488 AC: 2948 AN: 60392

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

African (AFR) AF: 0.121 AC: 5038 AN: 41534

American (AMR) AF: 0.0515 AC: 787 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0858 AC: 298 AN: 3472

East Asian (EAS) AF: 0.0615 AC: 319 AN: 5190

South Asian (SAS) AF: 0.0824 AC: 398 AN: 4830

European-Finnish (FIN) AF: 0.0172 AC: 182 AN: 10606

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0307 AC: 2087 AN: 68022

Other (OTH) AF: 0.0535 AC: 113 AN: 2112

Alfa AF: 0.0445 Hom.: 406

Bravo AF: 0.0642

Asia WGS AF: 0.0830 AC: 288 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	6.1
DANN	Benign	0.54
PhyloP100		0.38
Mutation Taster		=98/2	polymorphism (auto)

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