11-72358940-C-T

Position:

• chr11-72358940-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030813.6(CLPB):​c.805G>A​(p.Ala269Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CLPB NM_030813.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 4.87

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLPB	NM_030813.6	c.805G>A	p.Ala269Thr	missense_variant	6/17	ENST00000294053.9	NP_110440.1
CLPB	NM_001258392.3	c.715G>A	p.Ala239Thr	missense_variant	5/16	ENST00000538039.6	NP_001245321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLPB	ENST00000294053.9	c.805G>A	p.Ala269Thr	missense_variant	6/17	1	NM_030813.6	ENSP00000294053	P4
CLPB	ENST00000538039.6	c.715G>A	p.Ala239Thr	missense_variant	5/16	2	NM_001258392.3	ENSP00000441518	A1
	ENST00000537727.1	n.377+3592C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-methylglutaconic aciduria, type VIIB Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 08, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. ClinVar contains an entry for this variant (Variation ID: 279605). This missense change has been observed in individual(s) with CLPB-related conditions (PMID: 26916670). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 269 of the CLPB protein (p.Ala269Thr). -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;.;.;T;.;.;.;T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;.;.;D;D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D;D;D;D;D;.;.;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;.;.;.;D;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.
Vest4		0.67
MutPred		0.62		Gain of methylation at K265 (P = 0.1308);.;.;.;.;Gain of methylation at K265 (P = 0.1308);.;.;.;Gain of methylation at K265 (P = 0.1308);
MVP		0.80
MPC		1.1
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.55
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs886041117; hg19: chr11-72069984;