Genetic Variant TMLHE:p.Arg398His (chrX-155491608-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_018196.4(TMLHE):c.1193G>A(p.Arg398His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 0 hem., cov: 8)

Exomes 𝑓: 0.00010 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

TMLHE
NM_018196.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.76

Variant links:

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 links:

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

TMLHE-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMLHE	NM_018196.4 link	c.1193G>A	p.Arg398His	missense_variant	Exon 8 of 8	ENST00000334398.8	NP_060666.1	Q9NVH6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMLHE	ENST00000334398.8 link	c.1193G>A	p.Arg398His	missense_variant	Exon 8 of 8	1	NM_018196.4	ENSP00000335261.3		Q9NVH6-1

Frequencies

GnomAD3 genomes

AF:

0.0000542

AC:

AN:

55309

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

8863

show subpopulations

Gnomad AFR

AF:

0.0000606

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:

0.0000744

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000891

AC:

AN:

78574

Hom.:

AF XY:

0.00

AC XY:

AN XY:

21648

show subpopulations

Gnomad AFR exome

AF:

0.000302

Gnomad AMR exome

AF:

0.0000835

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.000168

Gnomad NFE exome

AF:

0.0000624

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000101

AC:

AN:

336788

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

92838

show subpopulations

Gnomad4 AFR exome

AF:

0.000100

Gnomad4 AMR exome

AF:

0.0000773

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:

0.000134

Gnomad4 OTH exome

AF:

0.000167

GnomAD4 genome

AF:

0.0000542

AC:

AN:

55309

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

8863

show subpopulations

Gnomad4 AFR

AF:

0.0000606

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000744

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000443

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1193G>A (p.R398H) alteration is located in exon 8 (coding exon 7) of the TMLHE gene. This alteration results from a G to A substitution at nucleotide position 1193, causing the arginine (R) at amino acid position 398 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.59

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.8

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.83

MutPred

0.97

Loss of sheet (P = 0.0817);

MVP

0.78

MPC

0.98

ClinPred

0.66

GERP RS

3.6

Varity_R

0.77

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over