Genetic Variant TMLHE:p.Ile321Ile (chrX-155506930-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_018196.4(TMLHE):c.963C>T(p.Ile321Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,207,353 control chromosomes in the GnomAD database, including 3 homozygotes. There are 132 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.00021 ( 3 hom. 130 hem. )

Consequence

TMLHE
NM_018196.4 synonymous

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.49

Publications

0 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant X-155506930-G-A is Benign according to our data. Variant chrX-155506930-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3051170.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Hemizygotes in GnomAd4 at 2 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.963C>T	p.Ile321Ile	synonymous	Exon 6 of 8	NP_060666.1	Q9NVH6-1
	TMLHE	NM_001184797.2		c.963C>T	p.Ile321Ile	synonymous	Exon 6 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.963C>T	p.Ile321Ile	synonymous	Exon 6 of 8	ENSP00000335261.3	Q9NVH6-1
TMLHE	ENST00000369439.4	TSL:1	c.963C>T	p.Ile321Ile	synonymous	Exon 6 of 7	ENSP00000358447.4	Q9NVH6-2
TMLHE	ENST00000902557.1		c.1032C>T	p.Ile344Ile	synonymous	Exon 7 of 9	ENSP00000572616.1

Frequencies

GnomAD3 genomes

AF:

0.0000630

AC:

AN:

111084

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:

0.00223

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000470

AC:

AN:

182885

AF XY:

0.000769

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000213

AC:

234

AN:

1096216

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

130

AN XY:

362282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26332

American (AMR)

AF:

0.00

AC:

AN:

35105

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19310

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30174

South Asian (SAS)

AF:

0.00414

AC:

224

AN:

54086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4123

European-Non Finnish (NFE)

AF:

0.00000476

AC:

AN:

840564

Other (OTH)

AF:

0.000109

AC:

AN:

45999

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.0000630

AC:

AN:

111137

Hom.:

Cov.:

AF XY:

0.0000597

AC XY:

AN XY:

33515

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30699

American (AMR)

AF:

0.00

AC:

AN:

10438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3534

South Asian (SAS)

AF:

0.00224

AC:

AN:

2677

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5987

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52754

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

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:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TMLHE-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

6.7

(source)

DANN

Benign

0.71

PhyloP100

2.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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