rs141458508

chr11-72294103-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_030813.6(CLPB):c.1794G>A(p.Thr598=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000608 in 1,614,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (1 hom.)
• Consequence: CLPB NM_030813.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.74

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 11-72294103-C-T is Benign according to our data. Variant chr11-72294103-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 476193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.74 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPB	NM_030813.6	c.1794G>A	p.Thr598=	synonymous_variant	16/17	ENST00000294053.9
CLPB	NM_001258392.3	c.1704G>A	p.Thr568=	synonymous_variant	15/16	ENST00000538039.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPB	ENST00000294053.9	c.1794G>A	p.Thr598=	synonymous_variant	16/17	1	NM_030813.6	P4
CLPB	ENST00000538039.6	c.1704G>A	p.Thr568=	synonymous_variant	15/16	2	NM_001258392.3	A1

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 50 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000379 AC: 95 AN: 250796 Hom.: 0 AF XY: 0.000347 AC XY: 47 AN XY: 135564

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000602

Gnomad NFE exome AF: 0.000459

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000638 AC: 932 AN: 1461808 Hom.: 1 Cov.: 32 AF XY: 0.000624 AC XY: 454 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.000498

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000468

Gnomad4 NFE exome AF: 0.000745

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74504

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000311 Hom.: 0

Bravo AF: 0.000423

EpiCase AF: 0.000763

EpiControl AF: 0.000652

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	CLPB: BP4, BP7 -

3-methylglutaconic aciduria, type VIIB Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	3.3
Dann	Benign	0.78

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: rs141458508; hg19: chr11-72005147;