NM_018196.4:c.704C>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_018196.4(TMLHE):c.704C>A(p.Thr235Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000371 in 1,200,801 control chromosomes in the GnomAD database, including 1 homozygotes. There are 109 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., 55 hem., cov: 22)

Exomes 𝑓: 0.00021 ( 0 hom. 54 hem. )

Consequence

TMLHE
NM_018196.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.33

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03219667).

BP6

Variant X-155511727-G-T is Benign according to our data. Variant chrX-155511727-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 507632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-155511727-G-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 222 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMLHE	NM_018196.4 link	c.704C>A	p.Thr235Asn	missense_variant	Exon 5 of 8	ENST00000334398.8	NP_060666.1	Q9NVH6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMLHE	ENST00000334398.8 link	c.704C>A	p.Thr235Asn	missense_variant	Exon 5 of 8	1	NM_018196.4	ENSP00000335261.3	Q9NVH6-1
TMLHE	ENST00000369439.4 link	c.704C>A	p.Thr235Asn	missense_variant	Exon 5 of 7	1		ENSP00000358447.4	Q9NVH6-2
TMLHE	ENST00000675642.1 link	c.737C>A	p.Thr246Asn	missense_variant	Exon 6 of 9			ENSP00000502604.1	Q9NVH6-8
TMLHE-AS1	ENST00000452506.1 link	n.67+22338G>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.00199

AC:

222

AN:

111707

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

AN XY:

33945

show subpopulations

Gnomad AFR

AF:

0.00712

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000191

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000535

AC:

AN:

181208

Hom.:

AF XY:

0.000304

AC XY:

AN XY:

65876

show subpopulations

Gnomad AFR exome

AF:

0.00730

Gnomad AMR exome

AF:

0.0000373

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:

0.00

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.000206

AC:

224

AN:

1089045

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

356035

show subpopulations

Gnomad4 AFR exome

AF:

0.00792

Gnomad4 AMR exome

AF:

0.000114

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:

0.00000120

Gnomad4 OTH exome

AF:

0.000241

GnomAD4 genome

AF:

0.00199

AC:

222

AN:

111756

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

AN XY:

34004

show subpopulations

Gnomad4 AFR

AF:

0.00711

Gnomad4 AMR

AF:

0.000191

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000244

Hom.:

Bravo

AF:

0.00242

ESP6500AA

AF:

0.00808

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000610

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 20, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

TMLHE-related disorder

Benign:1

Oct 27, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;.

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.032

T;T

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.6

H;H

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.98

D;D

Vest4

0.70

MVP

0.95

MPC

0.92

ClinPred

0.085

GERP RS

3.3

Varity_R

0.72

gMVP

0.81

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