rs587777616

Positions:

• chr11-57659895-G-A
• chr11-57659895-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_006831.3(CLP1):​c.419G>A​(p.Arg140His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CLP1 NM_006831.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• 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 Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.849
• PP5: Variant 11-57659895-G-A is Pathogenic according to our data. Variant chr11-57659895-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-57659895-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLP1	NM_006831.3	c.419G>A	p.Arg140His	missense_variant	2/3	ENST00000533682.2	NP_006822.1
CLP1	NM_001142597.2	c.414+5G>A		splice_donor_5th_base_variant, intron_variant			NP_001136069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLP1	ENST00000533682.2	c.419G>A	p.Arg140His	missense_variant	2/3	1	NM_006831.3	ENSP00000434995	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251204 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000198

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pontocerebellar hypoplasia type 10 Pathogenic:6

Likely pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Apr 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R140H in CLP1 (NM_006831.3) has been reported in multiple individuals of Turkish origin and has been classified as a Founder variant in the same population (Schaffer AE et al). Functional studies revealed a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.R140H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 140 of CLP1 is conserved in all mammalian species. The nucleotide c.419 in CLP1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Arg140His variant in CLP1 was identified by our study in one individual with pontocerebellar hypoplasia. This variant has been identified in 0.002978% (1/33574) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587777616). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The homozygous p.Arg140His variant in CLP1 has been reported in 19 Turkish individuals with cerebellar abnormalities and segregated with disease in 19 affected relatives from 9 families (PMID: 24766809, 24766810). In vitro functional studies provide some evidence that the p.Arg140His variant may impact protein function by impairing protein interaction with TSEN and reducing pre-tRNA cleavage activity. Northern blot analysis of individuals homozygous and heterozygous for this variant demonstrated increased levels of linear tRNA introns in individuals with the variant in the homozygous state (PMID: 24766809, 24766810). However, these types of assays may not accurately represent biological function. Animal models in zebrafish have shown that the wildtype gene, but not this variant, can rescue cerebellar neurodegeneration and animal models in mice have shown that this variant casues pontocerebellar hypoplasia (PMID: 24766809, 24766810). In summary, this variant meets criteria to be classified as pathogenic for Pontocerebellar Hypoplasia in an autosomal recessive manner based on evidence from in vitro functional studies, animal models in mice and zebrafish, and multiple occurrences of cosegregation in Turkish families. ACMG/AMP Criteria applied: PM2, PS3, PP1_Strong, PP3 (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences	May 27, 2023	The R140H variant in CLP1 gene has been identified in two Iranian families with seizure, brain and cerebellar atrophy, leukodystrophy, hypotonia, and developmental and motor delay. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 28, 2023	Criteria applied: PP1_STR,PS3_MOD,PM3,PM2_SUP,PP3 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CLP1: PP1:Strong, PM2, PM3, PS3:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.5	.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.89
MutPred		0.61		.;Loss of MoRF binding (P = 0.0104);Loss of MoRF binding (P = 0.0104);
MVP		0.62
MPC		1.8
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.89
gMVP		0.76

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;