rs113974315

chr2-43899580-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_133259.4(LRPPRC):c.3595A>G(p.Asn1199Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,611,096 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N1199N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0092 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (19 hom.)
• Consequence: LRPPRC NM_133259.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.59

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055610538).
• BP6: Variant 2-43899580-T-C is Benign according to our data. Variant chr2-43899580-T-C is described in ClinVar as [Benign]. Clinvar id is 214594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00919 (1400/152330) while in subpopulation AFR AF= 0.0318 (1321/41576). AF 95% confidence interval is 0.0303. There are 21 homozygotes in gnomad4. There are 653 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRPPRC	NM_133259.4	c.3595A>G	p.Asn1199Asp	missense_variant	33/38	ENST00000260665.12
LRPPRC	XM_006711915.3	c.3517A>G	p.Asn1173Asp	missense_variant	33/38
LRPPRC	XM_047442809.1	c.3469A>G	p.Asn1157Asp	missense_variant	33/38
LRPPRC	XR_007068563.1	n.3637A>G		non_coding_transcript_exon_variant	33/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRPPRC	ENST00000260665.12	c.3595A>G	p.Asn1199Asp	missense_variant	33/38	1	NM_133259.4	P3

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1400 AN: 152212 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00240 AC: 602 AN: 251074 Hom.: 9 AF XY: 0.00180 AC XY: 245 AN XY: 135742

Gnomad AFR exome AF: 0.0303

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000999 AC: 1458 AN: 1458766 Hom.: 19 Cov.: 29 AF XY: 0.000886 AC XY: 643 AN XY: 725960

Gnomad4 AFR exome AF: 0.0325

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.0000775

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00919 AC: 1400 AN: 152330 Hom.: 21 Cov.: 32 AF XY: 0.00877 AC XY: 653 AN XY: 74494

Gnomad4 AFR AF: 0.0318

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00188 Hom.: 8

Bravo AF: 0.0110

ESP6500AA AF: 0.0254 AC: 112

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.048
Sift	Benign	0.24	T
Sift4G	Benign	0.23	T
Polyphen		0.26	B
Vest4		0.29
MVP		0.34
MPC		0.025
ClinPred		0.0095	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs113974315; hg19: chr2-44126719;