NM_018196.4:c.1193G>A

Variant names:

• chrX-155491608-C-T
• rs782082408
• NM_018196.4:c.1193G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_018196.4(TMLHE):​c.1193G>A​(p.Arg398His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 0 hem., cov: 8)
  • Exomes 𝑓: 0.00010 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: TMLHE NM_018196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.76
• 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 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

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.1193G>A	p.Arg398His	missense	Exon 8 of 8	NP_060666.1	Q9NVH6-1
	TMLHE-AS1	NR_039991.1		n.472-1272C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMLHE	ENST00000334398.8	TSL:1 MANE Select	c.1193G>A	p.Arg398His	missense	Exon 8 of 8	ENSP00000335261.3	Q9NVH6-1
	TMLHE-AS1	ENST00000433624.1	TSL:1	n.472-1272C>T		intron	N/A
	TMLHE	ENST00000902557.1		c.1262G>A	p.Arg421His	missense	Exon 9 of 9	ENSP00000572616.1

Frequencies

GnomAD3 genomes AF: 0.0000542 AC: 3 AN: 55309 Hom.: 0 Cov.: 8

Gnomad AFR AF: 0.0000606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000744

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000891 AC: 7 AN: 78574 AF XY: 0.00

Gnomad AFR exome AF: 0.000302

Gnomad AMR exome AF: 0.0000835

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000168

Gnomad NFE exome AF: 0.0000624

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000101 AC: 34 AN: 336788 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 92838

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000100 AC: 1 AN: 9964

American (AMR) AF: 0.0000773 AC: 1 AN: 12940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9798

East Asian (EAS) AF: 0.00 AC: 0 AN: 17596

South Asian (SAS) AF: 0.00 AC: 0 AN: 29866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20455

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1378

European-Non Finnish (NFE) AF: 0.000134 AC: 29 AN: 216774

Other (OTH) AF: 0.000167 AC: 3 AN: 18017

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000105155), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000542 AC: 3 AN: 55309 Hom.: 0 Cov.: 8 AF XY: 0.00 AC XY: 0 AN XY: 8863

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000606 AC: 1 AN: 16495

American (AMR) AF: 0.00 AC: 0 AN: 5199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1614

East Asian (EAS) AF: 0.00 AC: 0 AN: 1889

South Asian (SAS) AF: 0.00 AC: 0 AN: 937

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 101

European-Non Finnish (NFE) AF: 0.0000744 AC: 2 AN: 26867

Other (OTH) AF: 0.00 AC: 0 AN: 707

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000907115), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000443 AC: 4

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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.97		Loss of sheet (P = 0.0817)
MVP		0.78
MPC		0.98
ClinPred		0.66	D
GERP RS		3.6
Varity_R		0.77
gMVP		0.71
Mutation Taster		=21/79	disease causing

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: rs782082408; hg19: chrX-154721269;