rs119477054

chr15-43082648-T-Achr15-43082648-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_174916.3(UBR1):c.407A>T(p.His136Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H136R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UBR1 NM_174916.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.24

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a zinc_finger_region UBR-type (size 71) in uniprot entity UBR1_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_174916.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-43082648-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 4678.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, UBR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBR1	NM_174916.3	c.407A>T	p.His136Leu	missense_variant	3/47	ENST00000290650.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBR1	ENST00000290650.9	c.407A>T	p.His136Leu	missense_variant	3/47	1	NM_174916.3	P1
UBR1	ENST00000546274.6	c.407A>T	p.His136Leu	missense_variant	3/29	2
UBR1	ENST00000563239.1	c.*54A>T		3_prime_UTR_variant, NMD_transcript_variant	2/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251268 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461330 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727000

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	25
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.89	D;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	4.0	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.8	D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.019	D;D
Polyphen		0.016	B;.
Vest4		0.94
MutPred		0.94		Loss of disorder (P = 0.0477);Loss of disorder (P = 0.0477);
MVP		0.88
MPC		0.65
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.97

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: rs119477054; hg19: chr15-43374846;