rs1555002798

chr11-57660909-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_006831.3(CLP1):c.751G>A(p.Val251Met) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLP1 NM_006831.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.81

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CLP1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLP1	NM_006831.3	c.751G>A	p.Val251Met	missense_variant	3/3	ENST00000533682.2
CLP1	NM_001142597.2	c.559G>A	p.Val187Met	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLP1	ENST00000533682.2	c.751G>A	p.Val251Met	missense_variant	3/3	1	NM_006831.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		1.0, 0.98	.;D;D;D
Vest4		0.81
MutPred		0.74		.;Loss of catalytic residue at V251 (P = 0.0045);Loss of catalytic residue at V251 (P = 0.0045);.;
MVP		0.73
MPC		1.5
ClinPred		0.95	D
GERP RS		5.9
Varity_R		0.80
gMVP		0.82

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: rs1555002798; hg19: chr11-57428381;