rs1555412542

Variant names:

• chr15-65157910-C-T
• rs1555412542
• NM_006660.5:c.893G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_006660.5(CLPX):​c.893G>A​(p.Gly298Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLPX NM_006660.5 missense, splice_region
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.76
• Publications: 0 publications found

Genes affected

CLPX (HGNC:2088): (caseinolytic mitochondrial matrix peptidase chaperone subunit X) The protein encoded by this gene is part of a protease found in mitochondria. This protease is ATP-dependent and targets specific proteins for degradation. The protease consists of two heptameric rings of the CLPP catalytic subunit sandwiched between two hexameric rings of the chaperone subunit encoded by this gene. Targeted proteins are unwound by this protein and then passed on to the CLPP subunit for degradation. Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Nov 2015]

CLPX Gene-Disease associations (from GenCC):

• protoporphyria, erythropoietic, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000299597 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 15-65157910-C-T is Pathogenic according to our data. Variant chr15-65157910-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 545573.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPX	NM_006660.5	c.893G>A	p.Gly298Asp	missense_variant, splice_region_variant	Exon 8 of 14	ENST00000300107.7	NP_006651.2
CLPX	XM_011521164.4	c.851G>A	p.Gly284Asp	missense_variant, splice_region_variant	Exon 7 of 13		XP_011519466.1
CLPX	NR_133680.2	n.970G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 14
CLPX	XR_931743.4	n.1082G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPX	ENST00000300107.7	c.893G>A	p.Gly298Asp	missense_variant, splice_region_variant	Exon 8 of 14	1	NM_006660.5	ENSP00000300107.3
CLPX	ENST00000558958.1	n.1082G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 9	1
CLPX	ENST00000559152.5	n.781G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 14	1		ENSP00000453461.1
ENSG00000299597	ENST00000764967.1	n.313+2925C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Protoporphyria, erythropoietic, 2 Pathogenic:2

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely Pathogenic, for Protoporphyria, erythropoietic, 2, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (https://www.uniprot.org/uniprot/O76031). PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/28874591). -

Jun 19, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.2	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.89		Loss of glycosylation at S297 (P = 0.0432);
MVP		0.94
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
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

Other links and lift over

dbSNP: rs1555412542; hg19: chr15-65450248;