3-126488206-G-A

Variant names:

• chr3-126488206-G-A
• rs139120643
• NM_144639.3:c.1782C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_144639.3(UROC1):​c.1782C>T​(p.Gly594Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,614,064 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G594G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: UROC1 NM_144639.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.847
• Publications: 3 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 3-126488206-G-A is Benign according to our data. Variant chr3-126488206-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 726175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

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.1782C>T	p.Gly594Gly	synonymous	Exon 18 of 20	NP_653240.1	Q96N76-1
	UROC1	NM_001165974.2		c.1962C>T	p.Gly654Gly	synonymous	Exon 19 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.1782C>T	p.Gly594Gly	synonymous	Exon 18 of 20	ENSP00000290868.2	Q96N76-1
	UROC1	ENST00000383579.3	TSL:1	c.1962C>T	p.Gly654Gly	synonymous	Exon 19 of 21	ENSP00000373073.3	Q96N76-2
	UROC1	ENST00000875183.1		c.1854C>T	p.Gly618Gly	synonymous	Exon 19 of 21	ENSP00000545242.1

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152090 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00196 AC: 493 AN: 251472 AF XY: 0.00213

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00276 AC: 4031 AN: 1461856 Hom.: 9 Cov.: 32 AF XY: 0.00274 AC XY: 1990 AN XY: 727226

African (AFR) AF: 0.000538 AC: 18 AN: 33478

American (AMR) AF: 0.000850 AC: 38 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 82 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00230 AC: 198 AN: 86258

European-Finnish (FIN) AF: 0.000730 AC: 39 AN: 53416

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00313 AC: 3481 AN: 1111984

Other (OTH) AF: 0.00275 AC: 166 AN: 60396

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152208 Hom.: 1 Cov.: 34 AF XY: 0.00179 AC XY: 133 AN XY: 74428

African (AFR) AF: 0.000433 AC: 18 AN: 41546

American (AMR) AF: 0.00151 AC: 23 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.000943 AC: 10 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00304 AC: 207 AN: 68006

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00227 Hom.: 0

Bravo AF: 0.00183

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.8
DANN	Benign	0.73
PhyloP100		-0.85
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.31		Position offset: -8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139120643; hg19: chr3-126207049; COSMIC: COSV52035663;