rs200101759

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_006012.4(CLPP):c.555+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000473 in 1,607,686 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 3 hom., cov: 30)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

CLPP
NM_006012.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.0002720

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.33

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 19-6364642-G-A is Benign according to our data. Variant chr19-6364642-G-A is described in ClinVar as [Benign]. Clinvar id is 226521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00253 (384/152014) while in subpopulation AFR AF= 0.0089 (369/41454). AF 95% confidence interval is 0.00815. There are 3 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPP	NM_006012.4 linkuse as main transcript	c.555+3G>A		splice_donor_region_variant, intron_variant		ENST00000245816.11
CLPP	XM_047439486.1 linkuse as main transcript	c.651+3G>A		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPP	ENST00000245816.11 linkuse as main transcript	c.555+3G>A		splice_donor_region_variant, intron_variant		1	NM_006012.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00253

AC:

384

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000657

AC:

159

AN:

241924

Hom.:

AF XY:

0.000462

AC XY:

AN XY:

132040

show subpopulations

Gnomad AFR exome

AF:

0.00912

Gnomad AMR exome

AF:

0.000379

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000511

Gnomad NFE exome

AF:

0.00000922

Gnomad OTH exome

AF:

0.000505

GnomAD4 exome

AF:

0.000259

AC:

377

AN:

1455672

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

723762

show subpopulations

Gnomad4 AFR exome

AF:

0.00912

Gnomad4 AMR exome

AF:

0.000606

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.0000199

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000581

GnomAD4 genome

AF:

0.00253

AC:

384

AN:

152014

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00890

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.00269

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	555+3G>A in intron 4 of CLPP: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (25/4406) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs200101759). -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

Cadd

Benign

Dann

Benign

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00027

dbscSNV1_RF

Benign

0.012

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over