rs72556258

Positions:

• chrX-38401297-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1 PP3_Strong BS2

The ENST00000039007.5(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 ENST00000039007.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• 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]

ACMG classification

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 ENST00000039007.5
• 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	Protein	UniProt
OTC	NM_000531.6	c.409G>A	p.Ala137Thr	missense_variant	5/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.409G>A	p.Ala137Thr	missense_variant	7/12		NP_001394021.1
OTC	XM_017029556.2	c.409G>A	p.Ala137Thr	missense_variant	5/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.409G>A	p.Ala137Thr	missense_variant	5/10	1	NM_000531.6	ENSP00000039007	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			ENSP00000496606

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182615 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67251

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000642 AC: 7 AN: 1090438 Hom.: 0 Cov.: 28 AF XY: 0.0000112 AC XY: 4 AN XY: 356184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000718

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 10, 2024

Variant summary: OTC c.409G>A (p.Ala137Thr) results in a non-conservative amino acid change located in the aspartate/ornithine carbamoyltransferase, carbamoyl-P binding domain (IPR006132) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182615 control chromosomes. c.409G>A has been reported in the literature in the heterozygous state in a female and in the hemizygous state in a male whose clinical presentations were not described (Yamaguchi_2006, Sharre_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Ornithine Transcarbamylase Deficiency. At least one in vitro study in COS-7 cells suggests that this variant results in residual enzyme activity of approximately 50% of wildtype and a yeast-based quantitative growth assay suggests that this variant is hypomorhpic and causes a deleterious clinical presentation (e.g. Sharre_2022, Lo_2023). The following publications have been ascertained in the context of this evaluation (PMID: 37146589, 36217298, 16786505). ClinVar contains an entry for this variant (Variation ID: 97193). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.025	D
Sift4G	Benign	0.26	T
Polyphen		0.76	P
Vest4		0.92
MutPred		0.87		Gain of sheet (P = 0.1208);
MVP		1.0
MPC		0.49
ClinPred		0.43	T
GERP RS		6.0
Varity_R		0.84
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs72556258; hg19: chrX-38260550;