rs144826521

chr2-43949659-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133259.4(LRPPRC):c.1678A>T(p.Ile560Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000752 in 1,612,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (1 hom.)
• Consequence: LRPPRC NM_133259.4 missense, splice_region
• Scores: Splicing: ADA: 0.5410
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 6.35

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1825876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRPPRC	NM_133259.4	c.1678A>T	p.Ile560Leu	missense_variant, splice_region_variant	16/38	ENST00000260665.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRPPRC	ENST00000260665.12	c.1678A>T	p.Ile560Leu	missense_variant, splice_region_variant	16/38	1	NM_133259.4	P3

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000685 AC: 172 AN: 251056 Hom.: 0 AF XY: 0.000693 AC XY: 94 AN XY: 135648

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000986

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000771 AC: 1126 AN: 1460454 Hom.: 1 Cov.: 29 AF XY: 0.000775 AC XY: 563 AN XY: 726614

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000877

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74480

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000971 Hom.: 0

Bravo AF: 0.000839

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.000709

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 20, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 560 of the LRPPRC protein (p.Ile560Leu). This variant is present in population databases (rs144826521, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Leigh syndrome (PMID: 34440436). ClinVar contains an entry for this variant (Variation ID: 214587). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2017	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 01, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 16, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	29
Dann	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Benign	0.24	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.44		Loss of helix (P = 0.0304);
MVP		0.51
MPC		0.076
ClinPred		0.075	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.21
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.12		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: rs144826521; hg19: chr2-44176798;