NM_018196.4:c.1178G>A

Variant names:

• chrX-155491623-C-T
• NM_018196.4:c.1178G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_018196.4(TMLHE):​c.1178G>A​(p.Cys393Tyr) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 10)
• Consequence: TMLHE NM_018196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57

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

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2644287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMLHE	NM_018196.4	c.1178G>A	p.Cys393Tyr	missense_variant	Exon 8 of 8	ENST00000334398.8	NP_060666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMLHE	ENST00000334398.8	c.1178G>A	p.Cys393Tyr	missense_variant	Exon 8 of 8	1	NM_018196.4	ENSP00000335261.3

Frequencies

GnomAD3 genomes Cov.: 10

GnomAD4 exome Cov.: 6

GnomAD4 genome Cov.: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1178G>A (p.C393Y) alteration is located in exon 8 (coding exon 7) of the TMLHE gene. This alteration results from a G to A substitution at nucleotide position 1178, causing the cysteine (C) at amino acid position 393 to be replaced by a tyrosine (Y). 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	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0	B
Vest4		0.25
MutPred		0.62		Loss of catalytic residue at R391 (P = 0.1435);
MVP		0.82
MPC		0.40
ClinPred		0.47	T
GERP RS		2.7
Varity_R		0.31
gMVP		0.43

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.

Other links and lift over

hg19: chrX-154721284;