NM_000531.6:c.374C>T

Variant names:

• chrX-38381417-C-T
• rs72554356
• NM_000531.6:c.374C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_000531.6(OTC):​c.374C>T​(p.Thr125Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000153 in 1,175,056 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 11 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:8
• Conservation: PhyloP100: -0.465
• Publications: 13 publications found

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]

OTC Gene-Disease associations (from GenCC):

• ornithine carbamoyltransferase deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000531.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 266 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 1.3274 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.
• BS2: High Hemizygotes in GnomAdExome4 at 11 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000531.6. 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
	OTC	NM_000531.6	MANE Select	c.374C>T	p.Thr125Met	missense	Exon 4 of 10	NP_000522.3
	OTC	NM_001407092.1		c.374C>T	p.Thr125Met	missense	Exon 6 of 12	NP_001394021.1	P00480

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.374C>T	p.Thr125Met	missense	Exon 4 of 10	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-284704C>T		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.374C>T	p.Thr125Met	missense	Exon 6 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111307 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 182605 AF XY: 0.0000298

Gnomad AFR exome AF: 0.0000762

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000160 AC: 17 AN: 1063696 Hom.: 0 Cov.: 26 AF XY: 0.0000331 AC XY: 11 AN XY: 332178

African (AFR) AF: 0.00 AC: 0 AN: 25796

American (AMR) AF: 0.0000285 AC: 1 AN: 35149

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19150

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30079

South Asian (SAS) AF: 0.0000375 AC: 2 AN: 53280

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40469

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4040

European-Non Finnish (NFE) AF: 0.0000111 AC: 9 AN: 810751

Other (OTH) AF: 0.0000667 AC: 3 AN: 44982

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111360 Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1 AN XY: 33594

African (AFR) AF: 0.0000327 AC: 1 AN: 30609

American (AMR) AF: 0.00 AC: 0 AN: 10447

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2645

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53109

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Ornithine carbamoyltransferase deficiency (4)
1	2	-	not provided (3)
-	1	-	Hyperammonemia (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	0.62
DANN	Benign	0.92
DEOGEN2	Uncertain	0.68	D
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.3	L
PhyloP100		-0.47
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.67	N
REVEL	Uncertain	0.59
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.69	P
Vest4		0.76
MVP		0.99
MPC		0.40
ClinPred		0.027	T
GERP RS		-3.0
Varity_R		0.13
gMVP		0.68
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs72554356; hg19: chrX-38240670;