rs863225443

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_133259.4(LRPPRC):​c.3900+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000207 in 1,448,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LRPPRC
NM_133259.4 splice_donor, intron

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.88
Variant links:
Genes affected
LRPPRC (HGNC:15714): (leucine rich pentatricopeptide repeat containing) This gene encodes a leucine-rich protein that has multiple pentatricopeptide repeats (PPR). The precise role of this protein is unknown but studies suggest it may play a role in cytoskeletal organization, vesicular transport, or in transcriptional regulation of both nuclear and mitochondrial genes. The protein localizes primarily to mitochondria and is predicted to have an N-terminal mitochondrial targeting sequence. Mutations in this gene are associated with the French-Canadian type of Leigh syndrome. [provided by RefSeq, Mar 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.017921148 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.3, offset of 36, new splice context is: actGTacgt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-43896633-C-A is Pathogenic according to our data. Variant chr2-43896633-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2203057.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LRPPRCNM_133259.4 linkc.3900+1G>T splice_donor_variant, intron_variant Intron 35 of 37 ENST00000260665.12 NP_573566.2 P42704E5KNY5
LRPPRCXM_006711915.3 linkc.3822+1G>T splice_donor_variant, intron_variant Intron 35 of 37 XP_006711978.1
LRPPRCXM_047442809.1 linkc.3774+1G>T splice_donor_variant, intron_variant Intron 35 of 37 XP_047298765.1
LRPPRCXR_007068563.1 linkn.3942+1G>T splice_donor_variant, intron_variant Intron 35 of 37

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRPPRCENST00000260665.12 linkc.3900+1G>T splice_donor_variant, intron_variant Intron 35 of 37 1 NM_133259.4 ENSP00000260665.7 P42704

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251398
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135876
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1448292
Hom.:
0
Cov.:
28
AF XY:
0.00000416
AC XY:
3
AN XY:
721400
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:
0.0000350
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Jul 07, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 35, but is expected to preserve the integrity of the reading-frame (PMID: 26510952). Disruption of this splice site has been observed in individuals with clinical features of Leigh Syndrome (PMID: 26510951). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects a donor splice site in intron 35 of the LRPPRC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
30
DANN
Uncertain
0.99
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.89
SpliceAI score (max)
0.85
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.85
Position offset: 1

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.

Other links and lift over

dbSNP: rs863225443; hg19: chr2-44123772; API