11-74493427-C-T

Variant names:

• chr11-74493427-C-T
• rs1864398589
• NM_001144869.3:c.277G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001144869.3(LIPT2):​c.277G>A​(p.Gly93Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,354,738 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: LIPT2 NM_001144869.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPT2	NM_001144869.3	c.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 2	ENST00000310109.5	NP_001138341.1
LIPT2	NM_001329941.2	c.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 2		NP_001316870.1
LIPT2	NM_001329942.2	c.237+40G>A		intron_variant	Intron 1 of 1		NP_001316871.1
LIPT2-AS1	NR_171028.1	n.48C>T		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.277G>A	p.Gly93Ser	missense_variant	Exon 1 of 2	2	NM_001144869.3	ENSP00000309463.4
LIPT2-AS1	ENST00000526036.1	n.62C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
LIPT2	ENST00000528085.1	c.180+40G>A		intron_variant	Intron 1 of 1	3		ENSP00000433005.1
LIPT2	ENST00000527115.1	c.-114G>A		upstream_gene_variant		2		ENSP00000431210.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000192 AC: 26 AN: 1354738 Hom.: 0 Cov.: 43 AF XY: 0.0000180 AC XY: 12 AN XY: 667962

Gnomad4 AFR exome AF: 0.0000359

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: 0.0000234

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.277G>A (p.G93S) alteration is located in exon 1 (coding exon 1) of the LIPT2 gene. This alteration results from a G to A substitution at nucleotide position 277, causing the glycine (G) at amino acid position 93 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.57	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.69		Gain of MoRF binding (P = 0.198);
MVP		0.31
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.85
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1864398589; hg19: chr11-74204472; COSMIC: COSV105902183; COSMIC: COSV105902183;