NM_006012.4:c.15A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

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. 15/21 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.219

Publications

0 publications found

Variant links:

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]

CLPP Gene-Disease associations (from GenCC):

Perrault syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
Perrault syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLPP links:

ENSG00000269802 (HGNC:):

ENSG00000269802 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 VariationId is 517633.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPP	NM_006012.4 link	c.15A>G	p.Ile5Met	missense_variant	Exon 1 of 6	ENST00000245816.11	NP_006003.1	Q16740
CLPP	XM_047439486.1 link	c.15A>G	p.Ile5Met	missense_variant	Exon 1 of 5		XP_047295442.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPP	ENST00000245816.11 link	c.15A>G	p.Ile5Met	missense_variant	Exon 1 of 6	1	NM_006012.4	ENSP00000245816.3		Q16740

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000182

AC:

AN:

54812

AF XY:

0.0000359

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000159

AC:

AN:

1256922

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

607814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24334

American (AMR)

AF:

0.00

AC:

AN:

16664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17364

East Asian (EAS)

AF:

0.0000674

AC:

AN:

29658

South Asian (SAS)

AF:

0.00

AC:

AN:

56796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4976

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1010986

Other (OTH)

AF:

0.00

AC:

AN:

51536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000181

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Apr 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 26, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.9

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.15

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.41

M_CAP

Benign

0.016

MetaRNN

Benign

0.0071

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.26

PhyloP100

0.22

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.070

REVEL

Benign

0.011

Sift

Benign

0.23

Sift4G

Pathogenic

0.0010

Polyphen

0.0010

Vest4

0.12

MutPred

0.44

Gain of disorder (P = 0.0155);

MVP

0.082

MPC

0.78

ClinPred

0.028

GERP RS

-2.2

PromoterAI

0.049

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.052

gMVP

0.11

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over