11-57659895-G-T

Position:

• chr11-57659895-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_006831.3(CLP1):​c.419G>T​(p.Arg140Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R140H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLP1 NM_006831.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.98

Genes affected

CLP1 (HGNC:16999): (cleavage factor polyribonucleotide kinase subunit 1) This gene encodes a member of the Clp1 family. The encoded protein is a multifunctional kinase which is a component of the tRNA splicing endonuclease complex and a component of the pre-mRNA cleavage complex II. This protein is implicated in tRNA, mRNA, and siRNA maturation. Mutations in this gene are associated with pontocerebellar hypoplasia type 10 (PCH10). Alternatively splice transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-57659895-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CLP1. . Gene score misZ 2.2535 (greater than the threshold 3.09). Trascript score misZ 3.2814 (greater than threshold 3.09). GenCC has associacion of gene with pontocerebellar hypoplasia type 10.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLP1	NM_006831.3	c.419G>T	p.Arg140Leu	missense_variant	2/3	ENST00000533682.2	NP_006822.1
CLP1	NM_001142597.2	c.414+5G>T		splice_region_variant, intron_variant			NP_001136069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLP1	ENST00000533682.2	c.419G>T	p.Arg140Leu	missense_variant	2/3	1	NM_006831.3	ENSP00000434995.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	.;L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.88
MutPred		0.60		.;Loss of MoRF binding (P = 0.0051);Loss of MoRF binding (P = 0.0051);
MVP		0.69
MPC		1.8
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.87
gMVP		0.85

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: rs587777616; hg19: chr11-57427367;