chr3-126482378-G-A

Variant names:

• chr3-126482378-G-A
• rs199712731
• NM_144639.3:c.1998C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_144639.3(UROC1):​c.1998C>T​(p.Asp666Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000429 in 1,613,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: UROC1 NM_144639.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.34
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-126482378-G-A is Benign according to our data. Variant chr3-126482378-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2654094.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.34 with no splicing effect.

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.1998C>T	p.Asp666Asp	synonymous	Exon 20 of 20	NP_653240.1	Q96N76-1
	UROC1	NM_001165974.2		c.2178C>T	p.Asp726Asp	synonymous	Exon 21 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.1998C>T	p.Asp666Asp	synonymous	Exon 20 of 20	ENSP00000290868.2	Q96N76-1
	UROC1	ENST00000383579.3	TSL:1	c.2178C>T	p.Asp726Asp	synonymous	Exon 21 of 21	ENSP00000373073.3	Q96N76-2
	UROC1	ENST00000875183.1		c.2070C>T	p.Asp690Asp	synonymous	Exon 21 of 21	ENSP00000545242.1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000310 AC: 77 AN: 248560 AF XY: 0.000326

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.000330

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000428 AC: 626 AN: 1461400 Hom.: 0 Cov.: 31 AF XY: 0.000437 AC XY: 318 AN XY: 726982

African (AFR) AF: 0.000269 AC: 9 AN: 33474

American (AMR) AF: 0.000157 AC: 7 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86222

European-Finnish (FIN) AF: 0.000677 AC: 36 AN: 53194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.000500 AC: 556 AN: 1111930

Other (OTH) AF: 0.000199 AC: 12 AN: 60372

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74468

African (AFR) AF: 0.000553 AC: 23 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000450 Hom.: 0

Bravo AF: 0.000382

EpiCase AF: 0.000327

EpiControl AF: 0.000475

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.0090
DANN	Benign	0.20
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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: rs199712731; hg19: chr3-126201221; COSMIC: COSV52036757;