Genetic Variant NM_133259.4:c.1678A>G (chr2-43949659-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_133259.4(LRPPRC):c.1678A>G(p.Ile560Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,460,464 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I560L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LRPPRC
NM_133259.4 missense, splice_region

Scores

Splicing: ADA: 0.6816

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.35

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

congenital lactic acidosis, Saguenay-Lac-Saint-Jean type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
cytochrome-c oxidase deficiency disease
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

LRPPRC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133259.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRPPRC	NM_133259.4	MANE Select	c.1678A>G	p.Ile560Val	missense splice_region	Exon 16 of 38	NP_573566.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LRPPRC	ENST00000260665.12	TSL:1 MANE Select	c.1678A>G	p.Ile560Val	missense splice_region	Exon 16 of 38	ENSP00000260665.7
LRPPRC	ENST00000447246.2	TSL:1	c.1678A>G	p.Ile560Val	missense splice_region	Exon 16 of 24	ENSP00000403637.2
LRPPRC	ENST00000683125.1		c.1678A>G	p.Ile560Val	missense splice_region	Exon 16 of 39	ENSP00000507939.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460464

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726618

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110812

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

3.0

PhyloP100

6.4

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.67

REVEL

Benign

0.21

Sift

Uncertain

0.014

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.62

MutPred

0.34

Loss of helix (P = 0.079)

MVP

0.56

MPC

0.13

ClinPred

0.89

GERP RS

5.9

Varity_R

0.14

gMVP

0.17

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.68

dbscSNV1_RF

Benign

0.52

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over