3-126483414-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_144639.3(UROC1):c.1845C>T(p.Ala615=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 1,613,264 control chromosomes in the GnomAD database, including 211,071 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.43 (15261 hom., cov: 34)
  • Exomes 𝑓: 0.51 (195810 hom.)
• Consequence: UROC1 NM_144639.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.72

Genes affected

UROC1 (HGNC:26444): (urocanate hydratase 1) This gene encodes an enzyme involved in the second step of histidine catabolism, metabolizing urocanic acid to formiminoglutamic acid. Deficiency of this enzyme results in urocanic aciduria, and is an apparent cause of mental retardation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2021]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-126483414-G-A is Benign according to our data. Variant chr3-126483414-G-A is described in ClinVar as [Benign]. Clinvar id is 130699.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-126483414-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UROC1	NM_144639.3	c.1845C>T	p.Ala615=	synonymous_variant	19/20	ENST00000290868.7
UROC1	NM_001165974.2	c.2025C>T	p.Ala675=	synonymous_variant	20/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UROC1	ENST00000290868.7	c.1845C>T	p.Ala615=	synonymous_variant	19/20	1	NM_144639.3	P1
UROC1	ENST00000383579.3	c.2025C>T	p.Ala675=	synonymous_variant	20/21	1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65187 AN: 152040 Hom.: 15257 Cov.: 34

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.713

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.442

GnomAD3 exomes AF: 0.480 AC: 120149 AN: 250440 Hom.: 29423 AF XY: 0.485 AC XY: 65804 AN XY: 135632

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.490

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.482

Gnomad SAS exome AF: 0.475

Gnomad FIN exome AF: 0.464

Gnomad NFE exome AF: 0.516

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.514 AC: 751057 AN: 1461108 Hom.: 195810 Cov.: 59 AF XY: 0.514 AC XY: 373790 AN XY: 726864

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.489

Gnomad4 ASJ exome AF: 0.483

Gnomad4 EAS exome AF: 0.441

Gnomad4 SAS exome AF: 0.479

Gnomad4 FIN exome AF: 0.460

Gnomad4 NFE exome AF: 0.534

Gnomad4 OTH exome AF: 0.494

GnomAD4 genome AF: 0.429 AC: 65200 AN: 152156 Hom.: 15261 Cov.: 34 AF XY: 0.427 AC XY: 31786 AN XY: 74384

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.493

Gnomad4 ASJ AF: 0.471

Gnomad4 EAS AF: 0.466

Gnomad4 SAS AF: 0.465

Gnomad4 FIN AF: 0.457

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.439

Alfa AF: 0.496 Hom.: 29265

Bravo AF: 0.427

Asia WGS AF: 0.405 AC: 1408 AN: 3478

EpiCase AF: 0.520

EpiControl AF: 0.514

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Urocanate hydratase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.037
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1687477; hg19: chr3-126202257; COSMIC: COSV52033201;