chrX-155507054-T-C

Variant names:

• chrX-155507054-T-C
• rs782761175
• NM_018196.4:c.839A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018196.4(TMLHE):​c.839A>G​(p.Gln280Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,057 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q280H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: TMLHE NM_018196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.117943704).

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.839A>G	p.Gln280Arg	missense	Exon 6 of 8	NP_060666.1	Q9NVH6-1
	TMLHE	NM_001184797.2		c.839A>G	p.Gln280Arg	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.839A>G	p.Gln280Arg	missense	Exon 6 of 8	ENSP00000335261.3	Q9NVH6-1
	TMLHE	ENST00000369439.4	TSL:1	c.839A>G	p.Gln280Arg	missense	Exon 6 of 7	ENSP00000358447.4	Q9NVH6-2
	TMLHE	ENST00000902557.1		c.908A>G	p.Gln303Arg	missense	Exon 7 of 9	ENSP00000572616.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182907 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097057 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 362983

African (AFR) AF: 0.00 AC: 0 AN: 26344

American (AMR) AF: 0.00 AC: 0 AN: 35119

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

East Asian (EAS) AF: 0.0000663 AC: 2 AN: 30182

South Asian (SAS) AF: 0.00 AC: 0 AN: 54107

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841293

Other (OTH) AF: 0.00 AC: 0 AN: 46034

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.26	N
PhyloP100		1.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.22
Sift	Benign	0.87	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.46		Loss of helix (P = 0.0626)
MVP		0.86
MPC		0.26
ClinPred		0.11	T
GERP RS		4.4
Varity_R		0.20
gMVP		0.46
Mutation Taster		=88/12	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: rs782761175; hg19: chrX-154736715;