chr11-72317205-G-A

Variant names:

• chr11-72317205-G-A
• rs148534573
• NM_030813.6:c.979C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001258392.3(CLPB):​c.889C>T​(p.Arg297Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000409 in 1,610,116 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R297Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: CLPB NM_001258392.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.41

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22947592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLPB	NM_030813.6	c.979C>T	p.Arg327Trp	missense_variant	Exon 8 of 17	ENST00000294053.9	NP_110440.1
CLPB	NM_001258392.3	c.889C>T	p.Arg297Trp	missense_variant	Exon 7 of 16	ENST00000538039.6	NP_001245321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLPB	ENST00000294053.9	c.979C>T	p.Arg327Trp	missense_variant	Exon 8 of 17	1	NM_030813.6	ENSP00000294053.3
CLPB	ENST00000538039.6	c.889C>T	p.Arg297Trp	missense_variant	Exon 7 of 16	2	NM_001258392.3	ENSP00000441518.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000243 AC: 60 AN: 246678 AF XY: 0.000247

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000179

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000454

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000426 AC: 621 AN: 1457982 Hom.: 1 Cov.: 30 AF XY: 0.000425 AC XY: 308 AN XY: 725230

Gnomad4 AFR exome AF: 0.0000599 AC: 2 AN: 33364

Gnomad4 AMR exome AF: 0.0000904 AC: 4 AN: 44272

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26028

Gnomad4 EAS exome AF: 0.0000760 AC: 3 AN: 39480

Gnomad4 SAS exome AF: 0.0000467 AC: 4 AN: 85656

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52562

Gnomad4 NFE exome AF: 0.000534 AC: 593 AN: 1110578

Gnomad4 Remaining exome AF: 0.000232 AC: 14 AN: 60288

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74318

Gnomad4 AFR AF: 0.000241 AC: 0.000241359 AN: 0.000241359

Gnomad4 AMR AF: 0.000131 AC: 0.000130941 AN: 0.000130941

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.000207555 AN: 0.000207555

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000353 AC: 0.000352806 AN: 0.000352806

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000419 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000932 AC: 8

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-methylglutaconic aciduria, type VIIB Uncertain:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 327 of the CLPB protein (p.Arg327Trp). This variant is present in population databases (rs148534573, gnomAD 0.04%). This missense change has been observed in individual(s) with severe congenital neutropenia (PMID: 34115842). ClinVar contains an entry for this variant (Variation ID: 542777). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect CLPB function (PMID: 34115842). 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. -

not provided Uncertain:1

Feb 14, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.;.;T;.;.;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;.;.;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;D;D;D;D;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.
Vest4		0.47
MVP		0.87
MPC		1.1
ClinPred		0.48	T
GERP RS		5.0
Varity_R		0.30
gMVP		0.64
Mutation Taster		=82/18	polymorphism

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: rs148534573; hg19: chr11-72028249; COSMIC: COSV53629765;