rs780400922

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS1

The NM_133259.4(LRPPRC):c.74G>A(p.Arg25His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,504,288 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000098 ( 1 hom. )

Consequence

LRPPRC
NM_133259.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6B:1

Conservation

PhyloP100: 3.18

Publications

3 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: G2P, Orphanet, 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
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

LRPPRC links:

ENSG00000288707 (HGNC:):

ENSG00000288707 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 9 uncertain in NM_133259.4

BP4

Computational evidence support a benign effect (MetaRNN=0.12581131).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000493 (75/152268) while in subpopulation AFR AF = 0.00154 (64/41570). AF 95% confidence interval is 0.00124. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRPPRC	NM_133259.4	MANE Select	c.74G>A	p.Arg25His	missense	Exon 1 of 38	NP_573566.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRPPRC	ENST00000260665.12	TSL:1 MANE Select	c.74G>A	p.Arg25His	missense	Exon 1 of 38	ENSP00000260665.7	P42704
LRPPRC	ENST00000447246.2	TSL:1	c.74G>A	p.Arg25His	missense	Exon 1 of 24	ENSP00000403637.2	C9JCA9
LRPPRC	ENST00000409946.6	TSL:1	c.74G>A	p.Arg25His	missense	Exon 1 of 14	ENSP00000386234.1	A0A0C4DG06

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000800

AC:

AN:

100034

AF XY:

0.0000714

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.0000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000544

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000976

AC:

132

AN:

1352020

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

666804

show subpopulations

African (AFR)

AF:

0.00198

AC:

AN:

27748

American (AMR)

AF:

0.0000935

AC:

AN:

32070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24078

East Asian (EAS)

AF:

0.00

AC:

AN:

31602

South Asian (SAS)

AF:

0.0000394

AC:

AN:

76076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33790

Middle Eastern (MID)

AF:

0.00198

AC:

AN:

4032

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

1066338

Other (OTH)

AF:

0.000284

AC:

AN:

56286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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

AF:

0.000493

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

41570

American (AMR)

AF:

0.000523

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000566

Hom.:

Bravo

AF:

0.000729

ExAC

AF:

0.000137

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (3)

not provided (3)

LRPPRC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.7

PhyloP100

3.2

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.5

REVEL

Benign

0.17

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.039

Polyphen

1.0

Vest4

0.49

MutPred

0.40

Loss of methylation at R25 (P = 0.0204)

MVP

0.61

MPC

0.021

ClinPred

0.13

GERP RS

4.3

PromoterAI

-0.036

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.19

gMVP

0.45

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over