rs912716897

Variant names:

• chr2-43918314-C-G
• rs912716897
• NM_133259.4:c.2981G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133259.4(LRPPRC):​c.2981G>C​(p.Arg994Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LRPPRC NM_133259.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.0370
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19437706).

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.2981G>C	p.Arg994Thr	missense	Exon 28 of 38	NP_573566.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRPPRC	ENST00000260665.12	TSL:1 MANE Select	c.2981G>C	p.Arg994Thr	missense	Exon 28 of 38	ENSP00000260665.7	P42704
	LRPPRC	ENST00000683125.1		c.3089G>C	p.Arg1030Thr	missense	Exon 29 of 39	ENSP00000507939.1	A0A804HKI2
	LRPPRC	ENST00000958038.1		c.2981G>C	p.Arg994Thr	missense	Exon 28 of 38	ENSP00000628097.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (1)
-	1	-	LRPPRC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.037
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.17
Sift	Benign	0.049	D
Sift4G	Benign	0.073	T
Polyphen		0.39	B
Vest4		0.43
MutPred		0.49		Loss of helix (P = 0.079)
MVP		0.36
MPC		0.024
ClinPred		0.95	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.71
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs912716897; hg19: chr2-44145453;