NM_018196.4:c.693C>T

Variant names:

• chrX-155511738-G-A
• NM_018196.4:c.693C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_018196.4(TMLHE):​c.693C>T​(p.Asp231Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,087,000 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: TMLHE NM_018196.4 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP7: Synonymous conserved (PhyloP=3.23 with no splicing effect.

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.693C>T	p.Asp231Asp	synonymous	Exon 5 of 8	NP_060666.1	Q9NVH6-1
	TMLHE	NM_001184797.2		c.693C>T	p.Asp231Asp	synonymous	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.693C>T	p.Asp231Asp	synonymous	Exon 5 of 8	ENSP00000335261.3	Q9NVH6-1
	TMLHE	ENST00000369439.4	TSL:1	c.693C>T	p.Asp231Asp	synonymous	Exon 5 of 7	ENSP00000358447.4	Q9NVH6-2
	TMLHE	ENST00000902557.1		c.762C>T	p.Asp254Asp	synonymous	Exon 6 of 9	ENSP00000572616.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1087000 Hom.: 0 Cov.: 28 AF XY: 0.00000282 AC XY: 1 AN XY: 354410

African (AFR) AF: 0.00 AC: 0 AN: 26235

American (AMR) AF: 0.0000286 AC: 1 AN: 34931

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19115

East Asian (EAS) AF: 0.00 AC: 0 AN: 30009

South Asian (SAS) AF: 0.00 AC: 0 AN: 52528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4086

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 834370

Other (OTH) AF: 0.00 AC: 0 AN: 45526

GnomAD4 genome Cov.: 22

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
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.3
DANN	Benign	0.91
PhyloP100		3.2

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

hg19: chrX-154741399;