X-155507099-G-A

Position:

• chrX-155507099-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018196.4(TMLHE):​c.794C>T​(p.Thr265Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,095,648 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: TMLHE NM_018196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 8.57

Genes affected

TMLHE (HGNC:18308): (trimethyllysine hydroxylase, epsilon) This gene encodes the protein trimethyllysine dioxygenase which is the first enzyme in the carnitine biosynthesis pathway. Carnitine play an essential role in the transport of activated fatty acids across the inner mitochondrial membrane. The encoded protein converts trimethyllysine into hydroxytrimethyllysine. A pseudogene of this gene is found on chromosome X. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

TMLHE-AS1 (HGNC:44261): (TMLHE antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMLHE	NM_018196.4	c.794C>T	p.Thr265Ile	missense_variant	6/8	ENST00000334398.8	NP_060666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMLHE	ENST00000334398.8	c.794C>T	p.Thr265Ile	missense_variant	6/8	1	NM_018196.4	ENSP00000335261	P1
TMLHE	ENST00000369439.4	c.794C>T	p.Thr265Ile	missense_variant	6/7	1		ENSP00000358447
TMLHE-AS1	ENST00000452506.1	n.67+17710G>A		intron_variant, non_coding_transcript_variant		5
TMLHE	ENST00000675642.1	c.827C>T	p.Thr276Ile	missense_variant	7/9			ENSP00000502604

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1095648 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 361774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 02, 2017

The T265I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T265I variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Epsilon-trimethyllysine hydroxylase deficiency Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Uncertain significance and reported on 01/00/1900 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		1.0	D;D
Vest4		0.52
MutPred		0.48		Gain of catalytic residue at L270 (P = 0.0329);Gain of catalytic residue at L270 (P = 0.0329);
MVP		0.95
MPC		0.90
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.57
gMVP		0.69

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: rs1557332788; hg19: chrX-154736760;