3-126498141-G-T

Variant names:

• chr3-126498141-G-T
• rs137852795
• NM_144639.3:c.1348C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The ENST00000290868.7(UROC1):​c.1348C>A​(p.Arg450Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R450C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: UROC1 ENST00000290868.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 0 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, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-126498141-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 407.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000290868.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROC1	NM_144639.3	MANE Select	c.1348C>A	p.Arg450Ser	missense	Exon 14 of 20	NP_653240.1
	UROC1	NM_001165974.2		c.1528C>A	p.Arg510Ser	missense	Exon 15 of 21	NP_001159446.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UROC1	ENST00000290868.7	TSL:1 MANE Select	c.1348C>A	p.Arg450Ser	missense	Exon 14 of 20	ENSP00000290868.2
	UROC1	ENST00000383579.3	TSL:1	c.1528C>A	p.Arg510Ser	missense	Exon 15 of 21	ENSP00000373073.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		9.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.95		Loss of glycosylation at S455 (P = 0.0891)
MVP		0.95
MPC		0.44
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.91
gMVP		0.98
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs137852795; hg19: chr3-126216984;