Genetic Variant TMLHE:p.Glu369Asp (chrX-155492384-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018196.4(TMLHE):c.1107G>T(p.Glu369Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 0)

Consequence

TMLHE
NM_018196.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 0.251

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01514402).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018196.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMLHE	NM_018196.4	MANE Select	c.1107G>T	p.Glu369Asp	missense	Exon 7 of 8	NP_060666.1
TMLHE-AS1	NR_039991.1		n.472-496C>A		intron	N/A
TMLHE	NM_001184797.2		c.*181G>T		downstream_gene	N/A	NP_001171726.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMLHE	ENST00000334398.8	TSL:1 MANE Select	c.1107G>T	p.Glu369Asp	missense	Exon 7 of 8	ENSP00000335261.3
TMLHE-AS1	ENST00000433624.1	TSL:1	n.472-496C>A		intron	N/A
TMLHE	ENST00000675642.1		c.1140G>T	p.Glu380Asp	missense	Exon 8 of 9	ENSP00000502604.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00206

AC:

AN:

17990

AF XY:

0.000246

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.000498

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000499

Hom.:

ExAC

AF:

0.000901

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Epsilon-trimethyllysine hydroxylase deficiency

Other:1

Oct 23, 2012

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.75

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.059

MutationAssessor

Pathogenic

3.4

PhyloP100

0.25

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.65

Sift

Uncertain

0.016

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.80

MutPred

0.48

Loss of catalytic residue at W371 (P = 0.0826)

MVP

0.54

MPC

0.82

ClinPred

0.16

GERP RS

1.4

Varity_R

0.57

gMVP

0.44

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over