chr2-99162088-A-G

Position:

chr2-99162088-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_145199.3(LIPT1):c.131A>G(p.Asn44Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,080 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

LIPT1
NM_145199.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: 9.11

Variant links:

Genes affected

LIPT1 (HGNC:29569): (lipoyltransferase 1) The process of transferring lipoic acid to proteins is a two-step process. The first step is the activation of lipoic acid by lipoate-activating enzyme to form lipoyl-AMP. For the second step, the protein encoded by this gene transfers the lipoyl moiety to apoproteins. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 13. Read-through transcription also exists between this gene and the neighboring downstream mitochondrial ribosomal protein L30 (MRPL30) gene. [provided by RefSeq, Mar 2011]

LIPT1 links:

MITD1 (HGNC:25207): (microtubule interacting and trafficking domain containing 1) Abscission, the separation of daughter cells at the end of cytokinesis, is effected by endosomal sorting complexes required for transport III (ESCRT-III). The protein encoded by this gene functions as a homodimer, with the N-termini binding to a subset of ESCRT-III subunits and the C-termini binding to membranes. The encoded protein regulates ESCRT-III activity and is required for proper cytokinesis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

MITD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

PP5

Variant 2-99162088-A-G is Pathogenic according to our data. Variant chr2-99162088-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPT1	NM_145199.3 linkuse as main transcript	c.131A>G	p.Asn44Ser	missense_variant	2/2	ENST00000651691.1	NP_660200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPT1	ENST00000651691.1 linkuse as main transcript	c.131A>G	p.Asn44Ser	missense_variant	2/2		NM_145199.3	ENSP00000498546	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251382

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135860

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727228

show subpopulations

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:

0.00000989

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2022

The c.131A>G (p.N44S) alteration is located in exon 3 (coding exon 1) of the LIPT1 gene. This alteration results from an A to G substitution at nucleotide position 131, causing the asparagine (N) at amino acid position 44 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (1/251382) total alleles studied. This alteration was detected in trans with a frameshift alteration in LIPT1 in an individual with abnormal development, seizures, lactic acidemia, hypotonia, along with 70% reduction in pyruvate dehydrogenase (PDH) activity in skin fibroblasts and low normal alpha dehydrogenase (AKGDH) activity (Ni, 2019). This amino acid position is highly conserved in available vertebrate species. In vitro and in vivo experimental studies show that this alteration led to abnormal lipoylation and impaired activation of PDH and AKGDH (Ni, 2019). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 05, 2022

The LIPT1 c.131A>G (p.Asn44Ser) missense variant results in the substitution of asparagine at amino acid position 44 with serine. The c.131A>G variant is reported compound heterozygous state with a nonsense variant in one affected individual in the literature, a child with abnormal development, seizures, and lactic acidemia and with two similarly affected siblings who were not genotyped (PMID: 31042466). Transfection of patient fibroblasts with the c.131A>G variant resulted in partial restoration of lipoylation and PDHA1 phosphorylation compare to transfection with the WT allele, suggesting it is hypomorphic allele (PMID: 31042466). A mouse model homozygous for the c.131A>G variant was not viable, but fetuses showed developmental and biochemical features consistent with the human phenotype (PMID: 31042466; PMID: 35388219). Additionally, the Asn44 residue is conserved and structural modelling suggests that it interacts with other conserved residues in the N-terminal domain (PMID: 31042466). The p.Asn44Ser variant is reported in one allele at a frequency of 0.00001470 in the European (non-Finnish) population of the Genome Aggregation Database (version 3.1.2). Based on the available evidence, c.131A>G (p.Asn44Ser) variant is classified as likely pathogenic for lipoyltransferase 1 deficiency. -

Lipoyl transferase 1 deficiency

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Baylor Genetics

Sep 01, 2017

Likely pathogenicity based on finding it twice in our laboratory in trans with a nonsense variant: in an 8-year-old female with low pyruvate dehydrogenase activity, intellectual disability, hearing loss, hypotoniea, epilepsy, microcephaly, failure to thrive, hepatopathy, anisocytosis, 2 deceased siblings similarly affected; in a 9-year-old female with spastic quadriparesis, single seizure, failure to thrive, scoliosis -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D;.;T;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;.;D;D;D

M_CAP

Uncertain

0.099

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

4.1

H;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.8

D;D;D;D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.96

MutPred

0.77

Gain of glycosylation at N44 (P = 0.0748);Gain of glycosylation at N44 (P = 0.0748);Gain of glycosylation at N44 (P = 0.0748);Gain of glycosylation at N44 (P = 0.0748);Gain of glycosylation at N44 (P = 0.0748);

MVP

0.69

ClinPred

1.0

GERP RS

4.9

Varity_R

0.77

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over