Genetic Variant TMLHE:p.Arg77* (chrX-155524585-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018196.4(TMLHE):c.229C>T(p.Arg77*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000932 in 1,202,187 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 32 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000097 ( 0 hom. 31 hem. )

Consequence

TMLHE
NM_018196.4 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 1.80

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BS2

High Hemizygotes in GnomAdExome4 at 31 Unknown,XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMLHE	NM_018196.4	MANE Select	c.229C>T	p.Arg77*	stop_gained	Exon 3 of 8	NP_060666.1	Q9NVH6-1
	TMLHE	NM_001184797.2		c.229C>T	p.Arg77*	stop_gained	Exon 3 of 7	NP_001171726.1	Q9NVH6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMLHE	ENST00000334398.8	TSL:1 MANE Select	c.229C>T	p.Arg77*	stop_gained	Exon 3 of 8	ENSP00000335261.3	Q9NVH6-1
TMLHE	ENST00000369439.4	TSL:1	c.229C>T	p.Arg77*	stop_gained	Exon 3 of 7	ENSP00000358447.4	Q9NVH6-2
TMLHE	ENST00000902557.1		c.298C>T	p.Arg100*	stop_gained	Exon 4 of 9	ENSP00000572616.1

Frequencies

GnomAD3 genomes

AF:

0.0000446

AC:

AN:

111986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000939

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000794

AC:

AN:

176349

AF XY:

0.0000489

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000312

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000753

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000972

AC:

106

AN:

1090147

Hom.:

Cov.:

AF XY:

0.0000870

AC XY:

AN XY:

356319

show subpopulations

African (AFR)

AF:

0.0000382

AC:

AN:

26197

American (AMR)

AF:

0.000348

AC:

AN:

34524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19186

East Asian (EAS)

AF:

0.00

AC:

AN:

29938

South Asian (SAS)

AF:

0.00

AC:

AN:

52014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

838070

Other (OTH)

AF:

0.000153

AC:

AN:

45766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000536

AC:

AN:

112040

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30837

American (AMR)

AF:

0.00

AC:

AN:

10595

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3568

South Asian (SAS)

AF:

0.00

AC:

AN:

2691

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6049

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53227

Other (OTH)

AF:

0.00

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000149

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability (1)

not provided (1)

Epsilon-trimethyllysine hydroxylase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Benign

0.75

PhyloP100

1.8

Vest4

0.41

GERP RS

2.0

Mutation Taster

=5/195

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over