11-72294395-T-G

Position:

• chr11-72294395-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The ENST00000294053.9(CLPB):​c.1700A>C​(p.Tyr567Ser) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y567C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLPB ENST00000294053.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.87

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000294053.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-72294395-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 279609.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2, not_provided=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLPB	NM_030813.6	c.1700A>C	p.Tyr567Ser	missense_variant	15/17	ENST00000294053.9	NP_110440.1
CLPB	NM_001258392.3	c.1610A>C	p.Tyr537Ser	missense_variant	14/16	ENST00000538039.6	NP_001245321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLPB	ENST00000294053.9	c.1700A>C	p.Tyr567Ser	missense_variant	15/17	1	NM_030813.6	ENSP00000294053	P4
CLPB	ENST00000538039.6	c.1610A>C	p.Tyr537Ser	missense_variant	14/16	2	NM_001258392.3	ENSP00000441518	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylglutaconic aciduria, type VIIB Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 05, 2022

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. This variant disrupts the p.Tyr567 amino acid residue in CLPB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25597510). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1045621). This missense change has been observed in individual(s) with 3-methylglutaconic aciduria (PMID: 32219827). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 567 of the CLPB protein (p.Tyr567Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;T;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.1	D;D;D;D;D;.;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;D;D;D;.;.
Sift4G	Uncertain	0.021	D;D;D;D;D;.;.
Polyphen		1.0	D;.;D;.;.;.;.
Vest4		0.89
MutPred		0.47		Gain of helix (P = 0.132);.;.;.;.;.;.;
MVP		0.55
MPC		1.4
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150857620; hg19: chr11-72005439;