Variant X-155506955-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018196.4(TMLHE):c.938T>C(p.Ile313Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,102 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

TMLHE
NM_018196.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.12

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10434273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMLHE	NM_018196.4 linkuse as main transcript	c.938T>C	p.Ile313Thr	missense_variant	6/8	ENST00000334398.8	NP_060666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMLHE	ENST00000334398.8 linkuse as main transcript	c.938T>C	p.Ile313Thr	missense_variant	6/8	1	NM_018196.4	ENSP00000335261	P1	Q9NVH6-1
TMLHE	ENST00000369439.4 linkuse as main transcript	c.938T>C	p.Ile313Thr	missense_variant	6/7	1		ENSP00000358447		Q9NVH6-2
TMLHE-AS1	ENST00000452506.1 linkuse as main transcript	n.67+17566A>G		intron_variant, non_coding_transcript_variant		5
TMLHE	ENST00000675642.1 linkuse as main transcript	c.971T>C	p.Ile324Thr	missense_variant	7/9			ENSP00000502604		Q9NVH6-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097102

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2024

The c.938T>C (p.I313T) alteration is located in exon 6 (coding exon 5) of the TMLHE gene. This alteration results from a T to C substitution at nucleotide position 938, causing the isoleucine (I) at amino acid position 313 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.096

T;.

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.24

N;N

MutationTaster

Benign

0.95

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.72

N;N

REVEL

Benign

0.20

Sift

Benign

0.46

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.0030

B;B

Vest4

0.21

MutPred

0.50

Loss of stability (P = 0.0116);Loss of stability (P = 0.0116);

MVP

0.61

MPC

0.31

ClinPred

0.23

GERP RS

3.2

Varity_R

0.089

gMVP

0.37

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over