rs1190703859

Variant names:

• chr11-74493390-A-C
• rs1190703859
• NM_001144869.3:c.314T>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001144869.3(LIPT2):​c.314T>G​(p.Leu105Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000198 in 1,515,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L105V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: LIPT2 NM_001144869.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.95
• Publications: 1 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 11-74493390-A-C is Pathogenic according to our data. Variant chr11-74493390-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 438641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.314T>G	p.Leu105Arg	missense	Exon 1 of 2	NP_001138341.1	A6NK58
	LIPT2	NM_001329941.2		c.314T>G	p.Leu105Arg	missense	Exon 1 of 2	NP_001316870.1
	LIPT2	NM_001329942.2		c.237+77T>G		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.314T>G	p.Leu105Arg	missense	Exon 1 of 2	ENSP00000309463.4	A6NK58
	LIPT2-AS1	ENST00000526036.1	TSL:1	n.25A>C		non_coding_transcript_exon	Exon 1 of 2
	LIPT2	ENST00000528085.1	TSL:3	c.180+77T>G		intron	N/A	ENSP00000433005.1	H0YD50

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.34e-7 AC: 1 AN: 1362864 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 672190

African (AFR) AF: 0.00 AC: 0 AN: 28496

American (AMR) AF: 0.00 AC: 0 AN: 33788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24490

East Asian (EAS) AF: 0.00 AC: 0 AN: 33194

South Asian (SAS) AF: 0.00 AC: 0 AN: 76684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5110

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070726

Other (OTH) AF: 0.00 AC: 0 AN: 57018

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152208 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

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

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.70
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.86		Gain of methylation at L105 (P = 0.0191)
MVP		0.57
ClinPred		1.0	D
GERP RS		3.1
PromoterAI		0.071	Neutral
Varity_R		0.97
gMVP		0.97
Mutation Taster		=25/75	disease causing (ClinVar)

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: rs1190703859; hg19: chr11-74204435;