rs763687804

chr19-6361589-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_006012.4(CLPP):c.15A>G(p.Ile5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 1,256,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: CLPP NM_006012.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.219

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070972443).
• BP6: Variant 19-6361589-A-G is Benign according to our data. Variant chr19-6361589-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517633.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPP	NM_006012.4	c.15A>G	p.Ile5Met	missense_variant	1/6	ENST00000245816.11
CLPP	XM_047439486.1	c.15A>G	p.Ile5Met	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPP	ENST00000245816.11	c.15A>G	p.Ile5Met	missense_variant	1/6	1	NM_006012.4	P1
	ENST00000595644.1	n.35+526T>C		intron_variant, non_coding_transcript_variant		4
CLPP	ENST00000596070.1	n.25A>G		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000182 AC: 1 AN: 54812 Hom.: 0 AF XY: 0.0000359 AC XY: 1 AN XY: 27870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000261

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000159 AC: 2 AN: 1256922 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 607814

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000674

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ExAC AF: 0.0000181 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 15, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 517633). This variant has not been reported in the literature in individuals affected with CLPP-related conditions. This variant is present in population databases (rs763687804, gnomAD 0.03%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 5 of the CLPP protein (p.Ile5Met). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 26, 2017

p.Ile5Met in exon 1 of CLPP: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , 7 mammals have a methionine (Met) at this position despite high nearby amino a cid conservation. In addition, computational prediction tools do not suggest a h igh likelihood of impact to the protein. It has been identified in 1/3416 of Eas t Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org; dbSNP rs763687804). ACMG/AMP Criteria applied: BP4 (Richards 2 015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.9
Dann	Benign	0.42
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.011
Sift	Benign	0.23	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.44		Gain of disorder (P = 0.0155);
MVP		0.082
MPC		0.78
ClinPred		0.028	T
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.052
gMVP		0.11

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: rs763687804; hg19: chr19-6361600;