chr11-72294645-T-A

Variant names:

• chr11-72294645-T-A
• rs373383193
• NM_030813.6:c.1625A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_001258392.3(CLPB):​c.1535A>T​(p.Glu512Val) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,614,184 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E512K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (38 hom.)
• Consequence: CLPB NM_001258392.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.99
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria, type VIIB

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• neutropenia, severe congenital, 9, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000255843 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 11-72294645-T-A is Benign according to our data. Variant chr11-72294645-T-A is described in ClinVar as Benign. ClinVar VariationId is 384977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000656 (100/152372) while in subpopulation SAS AF = 0.0192 (93/4834). AF 95% confidence interval is 0.0161. There are 1 homozygotes in GnomAd4. There are 70 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 38 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258392.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPB	NM_030813.6	MANE Plus Clinical	c.1625A>T	p.Glu542Val	missense	Exon 14 of 17	NP_110440.1	A0A140VK11
	CLPB	NM_001258392.3	MANE Select	c.1535A>T	p.Glu512Val	missense	Exon 13 of 16	NP_001245321.1	Q9H078-2
	CLPB	NM_001258394.3		c.1490A>T	p.Glu497Val	missense	Exon 15 of 18	NP_001245323.1	Q9H078-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPB	ENST00000294053.9	TSL:1 MANE Plus Clinical	c.1625A>T	p.Glu542Val	missense	Exon 14 of 17	ENSP00000294053.3	Q9H078-1
	CLPB	ENST00000538039.6	TSL:2 MANE Select	c.1535A>T	p.Glu512Val	missense	Exon 13 of 16	ENSP00000441518.1	Q9H078-2
	CLPB	ENST00000538021.5	TSL:1	n.*324A>T		non_coding_transcript_exon	Exon 6 of 9	ENSP00000445180.2	F6SS08

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 101 AN: 152254 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0194

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00242 AC: 608 AN: 251450 AF XY: 0.00327

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00122 AC: 1777 AN: 1461812 Hom.: 38 Cov.: 31 AF XY: 0.00175 AC XY: 1273 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0186 AC: 1603 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000827 AC: 92 AN: 1111944

Other (OTH) AF: 0.00126 AC: 76 AN: 60394

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152372 Hom.: 1 Cov.: 33 AF XY: 0.000939 AC XY: 70 AN XY: 74508

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.000196 AC: 3 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0192 AC: 93 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.00270 AC: 328

Asia WGS AF: 0.00837 AC: 31 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	3-methylglutaconic aciduria, type VIIB (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.52		Gain of MoRF binding (P = 0.028)
MVP		0.51
MPC		1.2
ClinPred		0.078	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.86
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.87		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373383193; hg19: chr11-72005689; COSMIC: COSV108102230;