2-43901773-C-T

Variant names:

• chr2-43901773-C-T
• rs4953032
• NM_133259.4:c.3365-249G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133259.4(LRPPRC):​c.3365-249G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 470,732 control chromosomes in the GnomAD database, including 59,803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21602 hom., cov: 32)
  • Exomes 𝑓: 0.47 (38201 hom.)
• Consequence: LRPPRC NM_133259.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.597
• Publications: 10 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 (BayesDel_noAF=-0.89).
• BP6: Variant 2-43901773-C-T is Benign according to our data. Variant chr2-43901773-C-T is described in ClinVar as Benign. ClinVar VariationId is 671284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

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.3365-249G>A		intron	N/A	NP_573566.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRPPRC	ENST00000260665.12	TSL:1 MANE Select	c.3365-249G>A		intron	N/A	ENSP00000260665.7	P42704
	LRPPRC	ENST00000683125.1		c.3473-249G>A		intron	N/A	ENSP00000507939.1	A0A804HKI2
	LRPPRC	ENST00000958038.1		c.3365-210G>A		intron	N/A	ENSP00000628097.1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77789 AN: 151758 Hom.: 21551 Cov.: 32

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.953

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.527

GnomAD4 exome AF: 0.467 AC: 149041 AN: 318858 Hom.: 38201 Cov.: 0 AF XY: 0.466 AC XY: 78931 AN XY: 169240

African (AFR) AF: 0.688 AC: 6747 AN: 9806

American (AMR) AF: 0.616 AC: 7977 AN: 12956

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 4064 AN: 9982

East Asian (EAS) AF: 0.939 AC: 19843 AN: 21128

South Asian (SAS) AF: 0.487 AC: 17108 AN: 35158

European-Finnish (FIN) AF: 0.422 AC: 6736 AN: 15980

Middle Eastern (MID) AF: 0.448 AC: 621 AN: 1386

European-Non Finnish (NFE) AF: 0.399 AC: 77285 AN: 193808

Other (OTH) AF: 0.464 AC: 8660 AN: 18654

GnomAD4 genome AF: 0.513 AC: 77902 AN: 151874 Hom.: 21602 Cov.: 32 AF XY: 0.517 AC XY: 38355 AN XY: 74206

African (AFR) AF: 0.670 AC: 27777 AN: 41446

American (AMR) AF: 0.578 AC: 8819 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1331 AN: 3468

East Asian (EAS) AF: 0.953 AC: 4936 AN: 5182

South Asian (SAS) AF: 0.517 AC: 2482 AN: 4804

European-Finnish (FIN) AF: 0.400 AC: 4198 AN: 10506

Middle Eastern (MID) AF: 0.438 AC: 128 AN: 292

European-Non Finnish (NFE) AF: 0.393 AC: 26676 AN: 67898

Other (OTH) AF: 0.531 AC: 1121 AN: 2112

Alfa AF: 0.424 Hom.: 10416

Bravo AF: 0.536

Asia WGS AF: 0.709 AC: 2462 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.39
DANN	Benign	0.82
PhyloP100		-0.60
Mutation Taster		=100/0	polymorphism (auto)

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: rs4953032; hg19: chr2-44128912;