NM_001144869.3:c.308T>C

Variant names:

• chr11-74493396-A-G
• rs965475341
• NM_001144869.3:c.308T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001144869.3(LIPT2):​c.308T>C​(p.Leu103Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,363,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L103R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: LIPT2 NM_001144869.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41
• Publications: 0 publications found

Genes affected

LIPT2 (HGNC:37216): (lipoyl(octanoyl) transferase 2) This gene encodes a mitochondrial protein that catalyzes the transfer of octanoic acid to lipoate-dependent enzymes such as octanoyl-ACP. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

LIPT2-AS1 (HGNC:56172): (LIPT2 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144869.3. 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
	LIPT2	NM_001144869.3	MANE Select	c.308T>C	p.Leu103Pro	missense	Exon 1 of 2	NP_001138341.1	A6NK58
	LIPT2	NM_001329941.2		c.308T>C	p.Leu103Pro	missense	Exon 1 of 2	NP_001316870.1
	LIPT2	NM_001329942.2		c.237+71T>C		intron	N/A	NP_001316871.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPT2	ENST00000310109.5	TSL:2 MANE Select	c.308T>C	p.Leu103Pro	missense	Exon 1 of 2	ENSP00000309463.4	A6NK58
	LIPT2-AS1	ENST00000526036.1	TSL:1	n.31A>G		non_coding_transcript_exon	Exon 1 of 2
	LIPT2	ENST00000528085.1	TSL:3	c.180+71T>C		intron	N/A	ENSP00000433005.1	H0YD50

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000907 AC: 1 AN: 110312 AF XY: 0.0000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000240

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1363778 Hom.: 0 Cov.: 43 AF XY: 0.00000149 AC XY: 1 AN XY: 672716

African (AFR) AF: 0.00 AC: 0 AN: 28510

American (AMR) AF: 0.00 AC: 0 AN: 33890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24530

East Asian (EAS) AF: 0.00 AC: 0 AN: 33342

South Asian (SAS) AF: 0.00 AC: 0 AN: 76734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5096

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1071246

Other (OTH) AF: 0.00 AC: 0 AN: 57062

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.91		Loss of sheet (P = 0.0457)
MVP		0.63
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		0.073	Neutral
Varity_R		0.96
gMVP		0.97
Mutation Taster		=27/73	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: rs965475341; hg19: chr11-74204441;