rs781889971

Variant names:

• chrX-155524585-G-A
• rs781889971
• NM_018196.4:c.229C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-155524585-G-A
• chrX-155524585-G-T

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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 1.80
• Publications: 4 publications found

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-AS1 (HGNC:44261): (TMLHE antisense RNA 1)

ACMG classification

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

• BS2: High Hemizygotes in GnomAdExome4 at 31 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMLHE	NM_018196.4	c.229C>T	p.Arg77*	stop_gained	Exon 3 of 8	ENST00000334398.8	NP_060666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMLHE	ENST00000334398.8	c.229C>T	p.Arg77*	stop_gained	Exon 3 of 8	1	NM_018196.4	ENSP00000335261.3

Frequencies

GnomAD3 genomes AF: 0.0000446 AC: 5 AN: 111986 Hom.: 0 Cov.: 23

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: 14 AN: 176349 AF XY: 0.0000489

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.: 0 Cov.: 30 AF XY: 0.0000870 AC XY: 31 AN XY: 356319

African (AFR) AF: 0.0000382 AC: 1 AN: 26197

American (AMR) AF: 0.000348 AC: 12 AN: 34524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19186

East Asian (EAS) AF: 0.00 AC: 0 AN: 29938

South Asian (SAS) AF: 0.00 AC: 0 AN: 52014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.000103 AC: 86 AN: 838070

Other (OTH) AF: 0.000153 AC: 7 AN: 45766

GnomAD4 genome AF: 0.0000536 AC: 6 AN: 112040 Hom.: 0 Cov.: 23 AF XY: 0.0000292 AC XY: 1 AN XY: 34232

African (AFR) AF: 0.00 AC: 0 AN: 30837

American (AMR) AF: 0.00 AC: 0 AN: 10595

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2691

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6049

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53227

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.000149 Hom.: 3

Bravo AF: 0.0000756

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Oct 23, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R77X variant in the TMLHE gene has been reported previously in two male siblings with autism and moderate intellectual disability who had elevated 6-N-trimethyllysine, the TMLHE substrate; however, these individuals harbored additional variants in other x-linked genes that may also have contributed to the autism and intellectual disability (Nava et al., 2012). This variant may cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R77X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R77X as a variant of uncertain significance. -

Intellectual disability Uncertain:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.75	D
PhyloP100		1.8
Vest4		0.41
GERP RS		2.0
Mutation Taster		=5/195	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs781889971; hg19: chrX-154754246; COSMIC: COSV57687253;