chr3-126498141-G-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_144639.3(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.

• Frequency: Genomes: not found (cov: 34)
• Consequence: UROC1 NM_144639.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UROC1	NM_144639.3	c.1348C>A	p.Arg450Ser	missense_variant	Exon 14 of 20	ENST00000290868.7	NP_653240.1
UROC1	NM_001165974.2	c.1528C>A	p.Arg510Ser	missense_variant	Exon 15 of 21		NP_001159446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UROC1	ENST00000290868.7	c.1348C>A	p.Arg450Ser	missense_variant	Exon 14 of 20	1	NM_144639.3	ENSP00000290868.2
UROC1	ENST00000383579.3	c.1528C>A	p.Arg510Ser	missense_variant	Exon 15 of 21	1		ENSP00000373073.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	4.5	H;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-126216984;