rs143053584

Variant names:

• chr19-6364444-G-A
• rs143053584
• NM_006012.4:c.368-8G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-6364444-G-A
• chr19-6364444-G-C
• chr19-6364444-G-T

Variant summary

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

The NM_006012.4(CLPP):​c.368-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00797 in 1,601,524 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 30)
  • Exomes 𝑓: 0.0082 (80 hom.)
• Consequence: CLPP NM_006012.4 splice_region, intron
• Scores: Splicing: ADA: 0.00007057
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.17

Genes affected

CLPP (HGNC:2084): (caseinolytic mitochondrial matrix peptidase proteolytic subunit) The protein encoded by this gene belongs to the peptidase family S14 and hydrolyzes proteins into small peptides in the presence of ATP and magnesium. The protein is transported into mitochondrial matrix and is associated with the inner mitochondrial membrane. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-6364444-G-A is Benign according to our data. Variant chr19-6364444-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0058 (882/152084) while in subpopulation NFE AF= 0.00875 (595/67994). AF 95% confidence interval is 0.00817. There are 7 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPP	NM_006012.4	c.368-8G>A		splice_region_variant, intron_variant	Intron 3 of 5	ENST00000245816.11	NP_006003.1
CLPP	XM_047439486.1	c.464-8G>A		splice_region_variant, intron_variant	Intron 2 of 4		XP_047295442.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPP	ENST00000245816.11	c.368-8G>A		splice_region_variant, intron_variant	Intron 3 of 5	1	NM_006012.4	ENSP00000245816.3

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 882 AN: 151966 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00433

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00957

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00875

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00657 AC: 1495 AN: 227694 Hom.: 6 AF XY: 0.00661 AC XY: 824 AN XY: 124586

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00735

Gnomad EAS exome AF: 0.0000581

Gnomad SAS exome AF: 0.00534

Gnomad FIN exome AF: 0.00950

Gnomad NFE exome AF: 0.00913

Gnomad OTH exome AF: 0.00816

GnomAD4 exome AF: 0.00820 AC: 11883 AN: 1449440 Hom.: 80 Cov.: 31 AF XY: 0.00822 AC XY: 5923 AN XY: 720450

Gnomad4 AFR exome AF: 0.000964

Gnomad4 AMR exome AF: 0.00361

Gnomad4 ASJ exome AF: 0.00708

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00601

Gnomad4 FIN exome AF: 0.00950

Gnomad4 NFE exome AF: 0.00900

Gnomad4 OTH exome AF: 0.00881

GnomAD4 genome AF: 0.00580 AC: 882 AN: 152084 Hom.: 7 Cov.: 30 AF XY: 0.00541 AC XY: 402 AN XY: 74354

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.00957

Gnomad4 NFE AF: 0.00875

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00817 Hom.: 6

Bravo AF: 0.00504

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Feb 26, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 26, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CLPP: BP4, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

368-8G>A in intron 3 of CLPP: This variant is not expected to have clinical sign ificance because it has been identified in 1.0% (82/8590) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs143053584). -

CLPP-related disorder Benign:1

Mar 16, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.20
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.0
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: rs143053584; hg19: chr19-6364455;