15-65154930-A-G

Position:

• chr15-65154930-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_006660.5(CLPX):​c.1463T>C​(p.Ile488Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,614,104 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (3 hom.)
• Consequence: CLPX NM_006660.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.32

Genes affected

CLPX (HGNC:2088): (caseinolytic mitochondrial matrix peptidase chaperone subunit X) The protein encoded by this gene is part of a protease found in mitochondria. This protease is ATP-dependent and targets specific proteins for degradation. The protease consists of two heptameric rings of the CLPP catalytic subunit sandwiched between two hexameric rings of the chaperone subunit encoded by this gene. Targeted proteins are unwound by this protein and then passed on to the CLPP subunit for degradation. Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16611359).
• BP6: Variant 15-65154930-A-G is Benign according to our data. Variant chr15-65154930-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1640657.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 215 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLPX	NM_006660.5	c.1463T>C	p.Ile488Thr	missense_variant	11/14	ENST00000300107.7	NP_006651.2
CLPX	XM_011521164.4	c.1421T>C	p.Ile474Thr	missense_variant	10/13		XP_011519466.1
CLPX	NR_133680.2	n.1606T>C		non_coding_transcript_exon_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLPX	ENST00000300107.7	c.1463T>C	p.Ile488Thr	missense_variant	11/14	1	NM_006660.5	ENSP00000300107	P1
CLPX	ENST00000559152.5	c.*610T>C		3_prime_UTR_variant, NMD_transcript_variant	11/14	1		ENSP00000453461
CLPX	ENST00000560166.1	n.312T>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00141 AC: 354 AN: 251452 Hom.: 0 AF XY: 0.00141 AC XY: 191 AN XY: 135896

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00235 AC: 3432 AN: 1461884 Hom.: 3 Cov.: 31 AF XY: 0.00232 AC XY: 1688 AN XY: 727246

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00285

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74442

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00218 Hom.: 0

Bravo AF: 0.00152

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 05, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.51
MPC		1.3
ClinPred		0.053	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.81

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: rs35754835; hg19: chr15-65447268;