rs199674307

Variant names:

• chrX-155511733-G-A
• rs199674307
• NM_018196.4:c.698C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_018196.4(TMLHE):​c.698C>T​(p.Ala233Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,198,984 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 2 hem.)
• Consequence: TMLHE NM_018196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.67
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.698C>T	p.Ala233Val	missense	Exon 5 of 8	NP_060666.1	Q9NVH6-1
	TMLHE	NM_001184797.2		c.698C>T	p.Ala233Val	missense	Exon 5 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.698C>T	p.Ala233Val	missense	Exon 5 of 8	ENSP00000335261.3	Q9NVH6-1
	TMLHE	ENST00000369439.4	TSL:1	c.698C>T	p.Ala233Val	missense	Exon 5 of 7	ENSP00000358447.4	Q9NVH6-2
	TMLHE	ENST00000902557.1		c.767C>T	p.Ala256Val	missense	Exon 6 of 9	ENSP00000572616.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111678 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000953

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000166 AC: 3 AN: 181032 AF XY: 0.0000152

Gnomad AFR exome AF: 0.0000769

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: 0.00

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.0000120 AC: 13 AN: 1087306 Hom.: 0 Cov.: 28 AF XY: 0.00000564 AC XY: 2 AN XY: 354622

African (AFR) AF: 0.00 AC: 0 AN: 26225

American (AMR) AF: 0.0000286 AC: 1 AN: 34946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19143

East Asian (EAS) AF: 0.0000333 AC: 1 AN: 30030

South Asian (SAS) AF: 0.00 AC: 0 AN: 52653

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4088

European-Non Finnish (NFE) AF: 0.00000959 AC: 8 AN: 834454

Other (OTH) AF: 0.0000659 AC: 3 AN: 45547

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111678 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33920

African (AFR) AF: 0.0000325 AC: 1 AN: 30745

American (AMR) AF: 0.0000953 AC: 1 AN: 10488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3524

South Asian (SAS) AF: 0.00 AC: 0 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53062

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.94
MPC		0.86
ClinPred		0.71	D
GERP RS		3.3
Varity_R		0.69
gMVP		0.85
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs199674307; hg19: chrX-154741394;