X-155507053-C-G

Variant names:

• chrX-155507053-C-G
• rs199989202
• NM_018196.4:c.840G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018196.4(TMLHE):​c.840G>C​(p.Gln280His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,097,087 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q280R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: TMLHE NM_018196.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.368
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3201747).

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.840G>C	p.Gln280His	missense	Exon 6 of 8	NP_060666.1	Q9NVH6-1
	TMLHE	NM_001184797.2		c.840G>C	p.Gln280His	missense	Exon 6 of 7	NP_001171726.1	Q9NVH6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMLHE	ENST00000334398.8	TSL:1 MANE Select	c.840G>C	p.Gln280His	missense	Exon 6 of 8	ENSP00000335261.3	Q9NVH6-1
	TMLHE	ENST00000369439.4	TSL:1	c.840G>C	p.Gln280His	missense	Exon 6 of 7	ENSP00000358447.4	Q9NVH6-2
	TMLHE	ENST00000902557.1		c.909G>C	p.Gln303His	missense	Exon 7 of 9	ENSP00000572616.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1097087 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363005

African (AFR) AF: 0.00 AC: 0 AN: 26348

American (AMR) AF: 0.00 AC: 0 AN: 35118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19327

East Asian (EAS) AF: 0.00 AC: 0 AN: 30182

South Asian (SAS) AF: 0.00 AC: 0 AN: 54105

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841322

Other (OTH) AF: 0.00 AC: 0 AN: 46033

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.37
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.41
Sift	Benign	0.12	T
Sift4G	Benign	0.098	T
Polyphen		0.87	P
Vest4		0.28
MutPred		0.45		Loss of helix (P = 0.0626)
MVP		0.85
MPC		0.63
ClinPred		0.86	D
GERP RS		3.5
Varity_R		0.20
gMVP		0.51
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199989202; hg19: chrX-154736714;