chr11-74493396-A-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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.

• 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

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPT2	NM_001144869.3	c.308T>C	p.Leu103Pro	missense_variant	Exon 1 of 2	ENST00000310109.5	NP_001138341.1
LIPT2	NM_001329941.2	c.308T>C	p.Leu103Pro	missense_variant	Exon 1 of 2		NP_001316870.1
LIPT2	NM_001329942.2	c.237+71T>C		intron_variant	Intron 1 of 1		NP_001316871.1
LIPT2-AS1	NR_171028.1	n.17A>G		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPT2	ENST00000310109.5	c.308T>C	p.Leu103Pro	missense_variant	Exon 1 of 2	2	NM_001144869.3	ENSP00000309463.4
LIPT2-AS1	ENST00000526036.1	n.31A>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
LIPT2	ENST00000528085.1	c.180+71T>C		intron_variant	Intron 1 of 1	3		ENSP00000433005.1
LIPT2	ENST00000527115.1	c.-83T>C		upstream_gene_variant		2		ENSP00000431210.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000907 AC: 1 AN: 110312 Hom.: 0 AF XY: 0.0000164 AC XY: 1 AN XY: 61024

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.33e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
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
Varity_R		0.96
gMVP		0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs965475341; hg19: chr11-74204441;