3-126482378-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144639.3(UROC1):​c.1998C>G​(p.Asp666Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D666D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UROC1 NM_144639.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07703379).

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>G	p.Asp666Glu	missense	Exon 20 of 20	NP_653240.1	Q96N76-1
	UROC1	NM_001165974.2		c.2178C>G	p.Asp726Glu	missense	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>G	p.Asp666Glu	missense	Exon 20 of 20	ENSP00000290868.2	Q96N76-1
	UROC1	ENST00000383579.3	TSL:1	c.2178C>G	p.Asp726Glu	missense	Exon 21 of 21	ENSP00000373073.3	Q96N76-2
	UROC1	ENST00000875183.1		c.2070C>G	p.Asp690Glu	missense	Exon 21 of 21	ENSP00000545242.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.0010
DANN	Benign	0.62
DEOGEN2	Benign	0.044	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.95	L
PhyloP100		-1.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		0.016	B
Vest4		0.17
MutPred		0.39		Gain of helix (P = 0.0199)
MVP		0.23
MPC		0.067
ClinPred		0.17	T
GERP RS		-6.8
Varity_R		0.095
gMVP		0.74
Mutation Taster		=86/14	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;