11-72293194-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_030813.6(CLPB):c.*173G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 775,744 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (11 hom.)
• Consequence: CLPB NM_030813.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.327

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-72293194-C-G is Benign according to our data. Variant chr11-72293194-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1216908.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1606/152262) while in subpopulation AFR AF= 0.0373 (1549/41536). AF 95% confidence interval is 0.0357. There are 25 homozygotes in gnomad4. There are 751 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLPB	NM_001258392.3	c.*173G>C		3_prime_UTR_variant	16/16	ENST00000538039.6
CLPB	NM_030813.6	c.*173G>C		3_prime_UTR_variant	17/17	ENST00000294053.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLPB	ENST00000294053.9	c.*173G>C		3_prime_UTR_variant	17/17	1	NM_030813.6	P4
CLPB	ENST00000538039.6	c.*173G>C		3_prime_UTR_variant	16/16	2	NM_001258392.3	A1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1603 AN: 152144 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0373

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00106 AC: 664 AN: 623482 Hom.: 11 Cov.: 8 AF XY: 0.000943 AC XY: 301 AN XY: 319268

Gnomad4 AFR exome AF: 0.0357

Gnomad4 AMR exome AF: 0.00167

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000103

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000939

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.0105 AC: 1606 AN: 152262 Hom.: 25 Cov.: 32 AF XY: 0.0101 AC XY: 751 AN XY: 74448

Gnomad4 AFR AF: 0.0373

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00874 Hom.: 2

Bravo AF: 0.0118

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.0
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs79458542; hg19: chr11-72004238;