3-126483414-G-A

Variant names:

• chr3-126483414-G-A
• rs1687477
• NM_144639.3:c.1845C>T

Variant summary

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

The NM_144639.3(UROC1):​c.1845C>T​(p.Ala615Ala) 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.72
• Publications: 19 publications found

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]

UROC1 Gene-Disease associations (from GenCC):

• urocanic aciduria

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

ACMG classification

Our verdict: Benign. The variant received -21 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 VariationId is 130699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144639.3. 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
	UROC1	NM_144639.3	MANE Select	c.1845C>T	p.Ala615Ala	synonymous	Exon 19 of 20	NP_653240.1	Q96N76-1
	UROC1	NM_001165974.2		c.2025C>T	p.Ala675Ala	synonymous	Exon 20 of 21	NP_001159446.1	Q96N76-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROC1	ENST00000290868.7	TSL:1 MANE Select	c.1845C>T	p.Ala615Ala	synonymous	Exon 19 of 20	ENSP00000290868.2	Q96N76-1
	UROC1	ENST00000383579.3	TSL:1	c.2025C>T	p.Ala675Ala	synonymous	Exon 20 of 21	ENSP00000373073.3	Q96N76-2
	UROC1	ENST00000875183.1		c.1917C>T	p.Ala639Ala	synonymous	Exon 20 of 21	ENSP00000545242.1

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

GnomAD2 exomes AF: 0.480 AC: 120149 AN: 250440 AF XY: 0.485

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 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

African (AFR) AF: 0.225 AC: 7516 AN: 33476

American (AMR) AF: 0.489 AC: 21849 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.483 AC: 12627 AN: 26134

East Asian (EAS) AF: 0.441 AC: 17518 AN: 39698

South Asian (SAS) AF: 0.479 AC: 41289 AN: 86238

European-Finnish (FIN) AF: 0.460 AC: 24309 AN: 52858

Middle Eastern (MID) AF: 0.495 AC: 2856 AN: 5768

European-Non Finnish (NFE) AF: 0.534 AC: 593242 AN: 1111854

Other (OTH) AF: 0.494 AC: 29851 AN: 60380

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

African (AFR) AF: 0.231 AC: 9573 AN: 41508

American (AMR) AF: 0.493 AC: 7546 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1636 AN: 3472

East Asian (EAS) AF: 0.466 AC: 2409 AN: 5172

South Asian (SAS) AF: 0.465 AC: 2242 AN: 4822

European-Finnish (FIN) AF: 0.457 AC: 4837 AN: 10590

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35214 AN: 67976

Other (OTH) AF: 0.439 AC: 929 AN: 2116

Alfa AF: 0.482 Hom.: 48187

Bravo AF: 0.427

Asia WGS AF: 0.405 AC: 1408 AN: 3478

EpiCase AF: 0.520

EpiControl AF: 0.514

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Urocanate hydratase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.037
DANN	Benign	0.51
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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