chr2-43949659-T-A

Position:

chr2-43949659-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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:6B:3

Conservation

PhyloP100: 6.35

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]

LRPPRC links:

LRPPRC (HGNC:):

LRPPRC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
LRPPRC	NM_133259.4 linkuse as main transcript	c.1678A>T	p.Ile560Leu	missense_variant, splice_region_variant	16/38	ENST00000260665.12	NP_573566.2	P42704E5KNY5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRPPRC	ENST00000260665.12 linkuse as main transcript	c.1678A>T	p.Ile560Leu	missense_variant, splice_region_variant	16/38	1	NM_133259.4	ENSP00000260665.7		P42704

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000693

AC XY:

AN XY:

135648

show subpopulations

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.:

Cov.:

AF XY:

0.000775

AC XY:

563

AN XY:

726614

show subpopulations

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:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74480

show subpopulations

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.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2017	- -
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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

M_CAP

Benign

0.026

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.1

REVEL

Benign

0.24

Sift

Benign

0.24

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.81

MutPred

0.44

Loss of helix (P = 0.0304);

MVP

0.51

MPC

0.076

ClinPred

0.075

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

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