Variant chrX-155507054-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018196.4(TMLHE):c.839A>G(p.Gln280Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,057 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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. Q280H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

TMLHE
NM_018196.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.57

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.117943704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMLHE	NM_018196.4 linkuse as main transcript	c.839A>G	p.Gln280Arg	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.839A>G	p.Gln280Arg	missense_variant	6/8	1	NM_018196.4	P1	Q9NVH6-1
TMLHE	ENST00000369439.4 linkuse as main transcript	c.839A>G	p.Gln280Arg	missense_variant	6/7	1			Q9NVH6-2
TMLHE-AS1	ENST00000452506.1 linkuse as main transcript	n.67+17665T>C		intron_variant, non_coding_transcript_variant		5
TMLHE	ENST00000675642.1 linkuse as main transcript	c.872A>G	p.Gln291Arg	missense_variant	7/9				Q9NVH6-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000547

AC:

AN:

182907

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67599

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000273

AC:

AN:

1097057

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

362983

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000663

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

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

Dec 11, 2023

The c.839A>G (p.Q280R) alteration is located in exon 6 (coding exon 5) of the TMLHE gene. This alteration results from a A to G substitution at nucleotide position 839, causing the glutamine (Q) at amino acid position 280 to be replaced by an arginine (R). 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

0.080

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.11

T;.

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.26

N;N

MutationTaster

Benign

0.87

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.22

Sift

Benign

0.87

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.0

B;B

Vest4

0.12

MutPred

0.46

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

MVP

0.86

MPC

0.26

ClinPred

0.11

GERP RS

4.4

Varity_R

0.20

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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