rs1555098495

Variant names:

• chr11-72358891-A-G
• rs1555098495
• NM_030813.6:c.854T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030813.6(CLPB):​c.854T>C​(p.Leu285Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,393,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CLPB NM_030813.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78
• Publications: 0 publications found

Genes affected

CLPB (HGNC:30664): (ClpB family mitochondrial disaggregase) This gene belongs to the ATP-ases associated with diverse cellular activities (AAA+) superfamily. Members of this superfamily form ring-shaped homo-hexamers and have highly conserved ATPase domains that are involved in various processes including DNA replication, protein degradation and reactivation of misfolded proteins. All members of this family hydrolyze ATP through their AAA+ domains and use the energy generated through ATP hydrolysis to exert mechanical force on their substrates. In addition to an AAA+ domain, the protein encoded by this gene contains a C-terminal D2 domain, which is characteristic of the AAA+ subfamily of Caseinolytic peptidases to which this protein belongs. It cooperates with Hsp70 in the disaggregation of protein aggregates. Allelic variants of this gene are associated with 3-methylglutaconic aciduria, which causes cataracts and neutropenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

CLPB Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria, type VIIB

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neutropenia, severe congenital, 9, autosomal dominant

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

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255672 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPB	NM_030813.6	c.854T>C	p.Leu285Pro	missense_variant	Exon 6 of 17	ENST00000294053.9	NP_110440.1
CLPB	NM_001258392.3	c.764T>C	p.Leu255Pro	missense_variant	Exon 5 of 16	ENST00000538039.6	NP_001245321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPB	ENST00000294053.9	c.854T>C	p.Leu285Pro	missense_variant	Exon 6 of 17	1	NM_030813.6	ENSP00000294053.3
CLPB	ENST00000538039.6	c.764T>C	p.Leu255Pro	missense_variant	Exon 5 of 16	2	NM_001258392.3	ENSP00000441518.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1393746 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 692300

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31516

American (AMR) AF: 0.00 AC: 0 AN: 42616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23656

East Asian (EAS) AF: 0.00 AC: 0 AN: 33992

South Asian (SAS) AF: 0.00 AC: 0 AN: 85298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5394

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1067502

Other (OTH) AF: 0.00 AC: 0 AN: 55846

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylglutaconic aciduria, type VIIB Uncertain:1

Jul 15, 2017

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 do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CLPB-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 285 of the CLPB protein (p.Leu285Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.;T;.;.;.;T;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.2	H;.;.;.;.;.;.;.;.;.
PhyloP100		7.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;.;.;D;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D;D;D;.;.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;.;.;D;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.
Vest4		0.85
MutPred		0.81		Loss of stability (P = 0.0076);.;.;.;.;Loss of stability (P = 0.0076);.;.;.;Loss of stability (P = 0.0076);
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.94
gMVP		0.97
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1555098495; hg19: chr11-72069935;