Variant X-155507053-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_018196.4(TMLHE):c.840G>T(p.Gln280His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000029 in 1,208,196 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q280R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.000027 ( 0 hom. 11 hem. )

Consequence

TMLHE
NM_018196.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.368

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2866351).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMLHE	NM_018196.4 linkuse as main transcript	c.840G>T	p.Gln280His	missense_variant	6/8	ENST00000334398.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMLHE	ENST00000334398.8 linkuse as main transcript	c.840G>T	p.Gln280His	missense_variant	6/8	1	NM_018196.4	P1	Q9NVH6-1
TMLHE	ENST00000369439.4 linkuse as main transcript	c.840G>T	p.Gln280His	missense_variant	6/7	1			Q9NVH6-2
TMLHE-AS1	ENST00000452506.1 linkuse as main transcript	n.67+17664C>A		intron_variant, non_coding_transcript_variant		5
TMLHE	ENST00000675642.1 linkuse as main transcript	c.873G>T	p.Gln291His	missense_variant	7/9				Q9NVH6-8

Frequencies

GnomAD3 genomes

AF:

0.0000450

AC:

AN:

111109

Hom.:

Cov.:

AF XY:

0.0000897

AC XY:

AN XY:

33447

show subpopulations

Gnomad AFR

AF:

0.0000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000958

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:

0.0000379

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000219

AC:

AN:

182903

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67591

show subpopulations

Gnomad AFR exome

AF:

0.0000761

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:

0.0000368

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000273

AC:

AN:

1097087

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

363005

show subpopulations

Gnomad4 AFR exome

AF:

0.0000759

Gnomad4 AMR exome

AF:

0.0000285

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:

0.0000309

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000450

AC:

AN:

111109

Hom.:

Cov.:

AF XY:

0.0000897

AC XY:

AN XY:

33447

show subpopulations

Gnomad4 AFR

AF:

0.0000652

Gnomad4 AMR

AF:

0.0000958

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000379

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000793

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.840G>T (p.Q280H) alteration is located in exon 6 (coding exon 5) of the TMLHE gene. This alteration results from a G to T substitution at nucleotide position 840, causing the glutamine (Q) at amino acid position 280 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

Benign

0.19

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.29

T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

0.97

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.40

Sift

Benign

0.12

T;T

Sift4G

Benign

0.098

T;T

Polyphen

0.87

P;D

Vest4

0.28

MutPred

0.45

Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);

MVP

0.85

MPC

0.63

ClinPred

0.38

GERP RS

3.5

Varity_R

0.20

gMVP

0.51

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