chr2-43899580-T-C

Variant names:

• chr2-43899580-T-C
• rs113974315
• NM_133259.4:c.3595A>G

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict 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:6
• Conservation: PhyloP100: 1.59
• Publications: 5 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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.3595A>G	p.Asn1199Asp	missense	Exon 33 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.3595A>G	p.Asn1199Asp	missense	Exon 33 of 38	ENSP00000260665.7	P42704
	LRPPRC	ENST00000683125.1		c.3703A>G	p.Asn1235Asp	missense	Exon 34 of 39	ENSP00000507939.1	A0A804HKI2
	LRPPRC	ENST00000958038.1		c.3634A>G	p.Asn1212Asp	missense	Exon 33 of 38	ENSP00000628097.1

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

GnomAD2 exomes AF: 0.00240 AC: 602 AN: 251074 AF XY: 0.00180

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 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

African (AFR) AF: 0.0325 AC: 1085 AN: 33334

American (AMR) AF: 0.00210 AC: 94 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86166

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53394

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5710

European-Non Finnish (NFE) AF: 0.0000775 AC: 86 AN: 1109382

Other (OTH) AF: 0.00247 AC: 149 AN: 60296

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

African (AFR) AF: 0.0318 AC: 1321 AN: 41576

American (AMR) AF: 0.00346 AC: 53 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00394 Hom.: 17

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.6
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
Mutation Taster		=92/8	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: rs113974315; hg19: chr2-44126719;