2-43896633-C-G

Variant names:

• chr2-43896633-C-G
• rs863225443
• NM_133259.4:c.3900+1G>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_133259.4(LRPPRC):​c.3900+1G>C 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: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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-G is Pathogenic according to our data. Variant chr2-43896633-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 218165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRPPRC	NM_133259.4	c.3900+1G>C		splice_donor_variant, intron_variant	Intron 35 of 37	ENST00000260665.12	NP_573566.2
LRPPRC	XM_006711915.3	c.3822+1G>C		splice_donor_variant, intron_variant	Intron 35 of 37		XP_006711978.1
LRPPRC	XM_047442809.1	c.3774+1G>C		splice_donor_variant, intron_variant	Intron 35 of 37		XP_047298765.1
LRPPRC	XR_007068563.1	n.3942+1G>C		splice_donor_variant, intron_variant	Intron 35 of 37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRPPRC	ENST00000260665.12	c.3900+1G>C		splice_donor_variant, intron_variant	Intron 35 of 37	1	NM_133259.4	ENSP00000260665.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448292 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 721400

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: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type Pathogenic:2

Apr 02, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Feb 09, 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: 26510951). ClinVar contains an entry for this variant (Variation ID: 218165). Disruption of this splice site has been observed in individuals with Leigh syndrome (PMID: 26510951). This variant is not present in population databases (gnomAD no frequency). 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	0.63	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	31
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	0.88
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -35
DS_DL_spliceai		0.85		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863225443; hg19: chr2-44123772;