Genetic Variant CLYBL:p.Arg87Gln (chr13-99858871-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_206808.5(CLYBL):c.260G>A(p.Arg87Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,616 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CLYBL
NM_206808.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.41

Publications

0 publications found

Variant links:

Genes affected

CLYBL (HGNC:18355): (citramalyl-CoA lyase) Enables (S)-citramalyl-CoA lyase activity; magnesium ion binding activity; and malate synthase activity. Involved in protein homotrimerization and regulation of cobalamin metabolic process. Predicted to be located in mitochondrion. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

CLYBL links:

ENSG00000286757 (HGNC:):

ENSG00000286757 links:

CLYBL-AS3 (HGNC:56191): (CLYBL antisense RNA 3)

CLYBL-AS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLYBL	NM_206808.5 link	c.260G>A	p.Arg87Gln	missense_variant	Exon 3 of 9	ENST00000339105.9	NP_996531.1	Q8N0X4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLYBL	ENST00000339105.9 link	c.260G>A	p.Arg87Gln	missense_variant	Exon 3 of 9	1	NM_206808.5	ENSP00000342991.4		Q8N0X4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000416

AC:

AN:

240204

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448616

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32676

American (AMR)

AF:

0.00

AC:

AN:

41644

Ashkenazi Jewish (ASJ)

AF:

0.0000393

AC:

AN:

25468

East Asian (EAS)

AF:

0.00

AC:

AN:

39494

South Asian (SAS)

AF:

0.00

AC:

AN:

83366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53266

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107254

Other (OTH)

AF:

0.00

AC:

AN:

59768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 10, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.260G>A (p.R87Q) alteration is located in exon 3 (coding exon 3) of the CLYBL gene. This alteration results from a G to A substitution at nucleotide position 260, causing the arginine (R) at amino acid position 87 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

T;.;T;T;T

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

.;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

4.2

H;H;H;.;.

PhyloP100

9.4

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.9

D;D;D;D;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;.;.

Vest4

0.96

MutPred

0.78

Gain of ubiquitination at K83 (P = 0.0598);Gain of ubiquitination at K83 (P = 0.0598);Gain of ubiquitination at K83 (P = 0.0598);.;.;

MVP

0.96

ClinPred

1.0

GERP RS

5.9

PromoterAI

-0.0026

Neutral

(source)

Varity_R

0.96

gMVP

0.87

Mutation Taster

=19/81

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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13-99858871-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over