rs748010262

Variant names:

• chr11-72294125-G-A
• rs748010262
• NM_030813.6:c.1772C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-72294125-G-A
• chr11-72294125-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001258392.3(CLPB):​c.1682C>T​(p.Ala561Val) 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLPB NM_001258392.3 missense, splice_region
• Scores: Splicing: ADA: 0.9821
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.69

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 11-72294125-G-A is Pathogenic according to our data. Variant chr11-72294125-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 187782.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-72294125-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPB	NM_030813.6	c.1772C>T	p.Ala591Val	missense_variant, splice_region_variant	Exon 16 of 17	ENST00000294053.9	NP_110440.1
CLPB	NM_001258392.3	c.1682C>T	p.Ala561Val	missense_variant, splice_region_variant	Exon 15 of 16	ENST00000538039.6	NP_001245321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPB	ENST00000294053.9	c.1772C>T	p.Ala591Val	missense_variant, splice_region_variant	Exon 16 of 17	1	NM_030813.6	ENSP00000294053.3
CLPB	ENST00000538039.6	c.1682C>T	p.Ala561Val	missense_variant, splice_region_variant	Exon 15 of 16	2	NM_001258392.3	ENSP00000441518.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Feb 05, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.;.;D;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D;.
REVEL	Pathogenic	0.77
Sift	Benign	0.21	T;T;T;T;T;.
Sift4G	Benign	0.12	T;T;T;T;T;.
Polyphen		0.98	D;.;P;.;.;.
Vest4		0.84
MutPred		0.59		Gain of MoRF binding (P = 0.1051);.;.;.;.;.;
MVP		0.60
MPC		1.2
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.60
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.76
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

Publications

LitVar

Other links and lift over

dbSNP: rs748010262; hg19: chr11-72005169;