rs72556258
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2
The NM_000531.6(OTC):c.409G>A(p.Ala137Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000642 in 1,090,438 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000064 ( 0 hom. 4 hem. )
Consequence
OTC
NM_000531.6 missense
NM_000531.6 missense
Scores
8
4
5
Clinical Significance
Conservation
PhyloP100: 3.61
Genes affected
OTC (HGNC:8512): (ornithine transcarbamylase) This nuclear gene encodes a mitochondrial matrix enzyme. The encoded protein is involved in the urea cycle which functions to detoxify ammonia into urea for excretion. Mutations in this enzyme lead to ornithine transcarbamylase deficiency, which causes hyperammonemia. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
?
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000531.6
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.988
BS2
?
High Hemizygotes in GnomAdExome4 at 4 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OTC | NM_000531.6 | c.409G>A | p.Ala137Thr | missense_variant | 5/10 | ENST00000039007.5 | |
OTC | NM_001407092.1 | c.409G>A | p.Ala137Thr | missense_variant | 7/12 | ||
OTC | XM_017029556.2 | c.409G>A | p.Ala137Thr | missense_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OTC | ENST00000039007.5 | c.409G>A | p.Ala137Thr | missense_variant | 5/10 | 1 | NM_000531.6 | P1 | |
OTC | ENST00000488812.1 | n.446G>A | non_coding_transcript_exon_variant | 5/6 | 5 | ||||
OTC | ENST00000643344.1 | c.*159G>A | 3_prime_UTR_variant, NMD_transcript_variant | 6/11 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD3 exomes AF: 0.00000548 AC: 1AN: 182615Hom.: 0 AF XY: 0.0000149 AC XY: 1AN XY: 67251
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GnomAD4 exome AF: 0.00000642 AC: 7AN: 1090438Hom.: 0 Cov.: 28 AF XY: 0.0000112 AC XY: 4AN XY: 356184
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
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Cov.:
23
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | GenMed Metabolism Lab | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of sheet (P = 0.1208);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at