Genetic Variant NM_018196.4:c.722G>A (chrX-155511709-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4BP6_ModerateBS2

The NM_018196.4(TMLHE):c.722G>A(p.Arg241Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000195 in 1,200,954 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 75 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 0.00015 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.00020 ( 0 hom. 70 hem. )

Consequence

TMLHE
NM_018196.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.11

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 (MetaRNN=0.29569468).

BP6

Variant X-155511709-C-T is Benign according to our data. Variant chrX-155511709-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2661879.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 5 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.722G>A	p.Arg241Gln	missense	Exon 5 of 8	NP_060666.1	Q9NVH6-1
	TMLHE	NM_001184797.2		c.722G>A	p.Arg241Gln	missense	Exon 5 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.722G>A	p.Arg241Gln	missense	Exon 5 of 8	ENSP00000335261.3	Q9NVH6-1
TMLHE	ENST00000369439.4	TSL:1	c.722G>A	p.Arg241Gln	missense	Exon 5 of 7	ENSP00000358447.4	Q9NVH6-2
TMLHE	ENST00000902557.1		c.791G>A	p.Arg264Gln	missense	Exon 6 of 9	ENSP00000572616.1

Frequencies

GnomAD3 genomes

AF:

0.000153

AC:

AN:

111330

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:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000302

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000210

AC:

AN:

180807

AF XY:

0.000168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000374

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000432

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000199

AC:

217

AN:

1089575

Hom.:

Cov.:

AF XY:

0.000196

AC XY:

AN XY:

356893

show subpopulations

African (AFR)

AF:

0.0000381

AC:

AN:

26256

American (AMR)

AF:

0.00

AC:

AN:

34969

Ashkenazi Jewish (ASJ)

AF:

0.0000523

AC:

AN:

19126

East Asian (EAS)

AF:

0.0000333

AC:

AN:

30064

South Asian (SAS)

AF:

0.0000948

AC:

AN:

52753

European-Finnish (FIN)

AF:

0.0000249

AC:

AN:

40239

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4096

European-Non Finnish (NFE)

AF:

0.000242

AC:

202

AN:

836420

Other (OTH)

AF:

0.000131

AC:

AN:

45652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.000153

AC:

AN:

111379

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

AN XY:

33643

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30682

American (AMR)

AF:

0.00

AC:

AN:

10463

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3511

South Asian (SAS)

AF:

0.00

AC:

AN:

2663

European-Finnish (FIN)

AF:

0.000166

AC:

AN:

6019

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000302

AC:

AN:

52979

Other (OTH)

AF:

0.00

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000145

Hom.:

Bravo

AF:

0.000178

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000206

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.30

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.3

PhyloP100

4.1

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.72

REVEL

Uncertain

0.43

Sift

Benign

0.080

Sift4G

Benign

0.090

Polyphen

1.0

Vest4

0.16

MVP

0.55

MPC

0.75

ClinPred

0.11

GERP RS

2.8

Varity_R

0.12

gMVP

0.74

Mutation Taster

=96/4

polymorphism

(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