rs143097446

chr11-72372993-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030813.6(CLPB):c.668G>A(p.Ser223Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,614,066 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (53 hom.)
• Consequence: CLPB NM_030813.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.22

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041360855).
• BP6: Variant 11-72372993-C-T is Benign according to our data. Variant chr11-72372993-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72372993-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00445 (677/152248) while in subpopulation NFE AF= 0.00739 (503/68022). AF 95% confidence interval is 0.00686. There are 3 homozygotes in gnomad4. There are 305 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPB	NM_030813.6	c.668G>A	p.Ser223Asn	missense_variant	5/17	ENST00000294053.9
CLPB	NM_001258392.3	c.646+7288G>A		intron_variant		ENST00000538039.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPB	ENST00000294053.9	c.668G>A	p.Ser223Asn	missense_variant	5/17	1	NM_030813.6	P4
CLPB	ENST00000538039.6	c.646+7288G>A		intron_variant		2	NM_001258392.3	A1

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 677 AN: 152130 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00739

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00461 AC: 1157 AN: 251248 Hom.: 4 AF XY: 0.00450 AC XY: 611 AN XY: 135772

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00702

Gnomad NFE exome AF: 0.00778

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00707 AC: 10328 AN: 1461818 Hom.: 53 Cov.: 30 AF XY: 0.00684 AC XY: 4976 AN XY: 727220

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00590

Gnomad4 NFE exome AF: 0.00860

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.00445 AC: 677 AN: 152248 Hom.: 3 Cov.: 32 AF XY: 0.00410 AC XY: 305 AN XY: 74438

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.00739

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00642 Hom.: 5

Bravo AF: 0.00423

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00676 AC: 58

ExAC AF: 0.00451 AC: 548

EpiCase AF: 0.00692

EpiControl AF: 0.00782

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2019	This variant is associated with the following publications: (PMID: 24439111) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CLPB: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 27, 2016

- -

3-methylglutaconic aciduria, type VIIB;C5676954:Neutropenia, severe congenital, 9, autosomal dominant;C5676967:3-methylglutaconic aciduria, type VIIA Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

3-methylglutaconic aciduria, type VIIB Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	20
Dann	Benign	0.67
DEOGEN2	Benign	0.028	T;.;T;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.70	T;T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0041	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;N;N
PROVEAN	Benign	-0.20	N;N;N;.;N;.
REVEL	Benign	0.018
Sift	Benign	0.037	D;D;D;.;T;.
Sift4G	Benign	0.23	T;T;T;.;T;.
Polyphen		0.019	B;.;.;.;.;.
Vest4		0.35
MVP		0.54
MPC		0.36
ClinPred		0.0048	T
GERP RS		2.2
Varity_R		0.051
gMVP		0.37

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: rs143097446; hg19: chr11-72084037; COSMIC: COSV53631255;