chr11-72293375-T-C

Position:

chr11-72293375-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030813.6(CLPB):c.2116A>G(p.Thr706Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000806 in 1,613,608 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T706T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0045 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 5 hom. )

Consequence

CLPB
NM_030813.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.74

Variant links:

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]

CLPB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005508572).

BP6

Variant 11-72293375-T-C is Benign according to our data. Variant chr11-72293375-T-C is described in ClinVar as [Benign]. Clinvar id is 384218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-72293375-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00449 (683/152124) while in subpopulation AFR AF= 0.0144 (596/41500). AF 95% confidence interval is 0.0134. There are 6 homozygotes in gnomad4. There are 323 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPB	NM_030813.6 linkuse as main transcript	c.2116A>G	p.Thr706Ala	missense_variant	17/17	ENST00000294053.9
CLPB	NM_001258392.3 linkuse as main transcript	c.2026A>G	p.Thr676Ala	missense_variant	16/16	ENST00000538039.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPB	ENST00000294053.9 linkuse as main transcript	c.2116A>G	p.Thr706Ala	missense_variant	17/17	1	NM_030813.6	P4	Q9H078-1
CLPB	ENST00000538039.6 linkuse as main transcript	c.2026A>G	p.Thr676Ala	missense_variant	16/16	2	NM_001258392.3	A1	Q9H078-2

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

659

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00107

AC:

268

AN:

251112

Hom.:

AF XY:

0.000774

AC XY:

105

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000422

AC:

617

AN:

1461484

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

283

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.0134

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.00449

AC:

683

AN:

152124

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

323

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0144

Gnomad4 AMR

AF:

0.00445

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000639

Hom.:

Bravo

AF:

0.00474

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00121

AC:

147

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CLPB: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

3-methylglutaconic aciduria, type VIIB

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

T;.;.;T;.;.

Eigen

Benign

-0.018

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.67

T;T;T;T;T;T

MetaRNN

Benign

0.0055

T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.4

L;.;.;.;.;.

MutationTaster

Benign

0.77

N;N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.66

N;N;N;N;N;.

REVEL

Benign

0.041

Sift

Uncertain

0.0050

D;D;D;D;D;.

Sift4G

Uncertain

0.031

D;D;D;D;D;.

Polyphen

0.039

B;.;B;.;.;.

Vest4

0.098

MVP

0.66

MPC

0.39

ClinPred

0.014

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.042

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over