rs75589928

chr19-6361570-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006012.4(CLPP):c.-5G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,398,188 control chromosomes in the GnomAD database, including 914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (417 hom., cov: 33)
  • Exomes 𝑓: 0.020 (497 hom.)
• Consequence: CLPP NM_006012.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0600

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-6361570-G-A is Benign according to our data. Variant chr19-6361570-G-A is described in ClinVar as [Benign]. Clinvar id is 226522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPP	NM_006012.4	c.-5G>A		5_prime_UTR_variant	1/6	ENST00000245816.11
CLPP	XM_047439486.1	c.-5G>A		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPP	ENST00000245816.11	c.-5G>A		5_prime_UTR_variant	1/6	1	NM_006012.4	P1
	ENST00000595644.1	n.35+545C>T		intron_variant, non_coding_transcript_variant		4
CLPP	ENST00000596070.1	n.6G>A		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7738 AN: 152200 Hom.: 418 Cov.: 33

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0473

GnomAD3 exomes AF: 0.0201 AC: 967 AN: 48062 Hom.: 26 AF XY: 0.0179 AC XY: 430 AN XY: 24012

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0135

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0151

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0202 AC: 25113 AN: 1245872 Hom.: 497 Cov.: 31 AF XY: 0.0200 AC XY: 12052 AN XY: 601202

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.0182

Gnomad4 ASJ exome AF: 0.0188

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0221

Gnomad4 FIN exome AF: 0.0146

Gnomad4 NFE exome AF: 0.0176

Gnomad4 OTH exome AF: 0.0242

GnomAD4 genome AF: 0.0508 AC: 7742 AN: 152316 Hom.: 417 Cov.: 33 AF XY: 0.0501 AC XY: 3731 AN XY: 74480

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0265

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0144

Gnomad4 NFE AF: 0.0184

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0319 Hom.: 26

Bravo AF: 0.0547

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	-5G>A in exon 1 of CLPP: This variant is not expected to have clinical significa nce because it has been identified in 10.8% (455/4208) of African American chrom osomes from a broad population by the NHLBI Exome Sequencing Project (http://evs .gs.washington.edu/EVS; dbSNP rs75589928). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2018	- -

Perrault syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	8.9
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75589928; hg19: chr19-6361581;