Genetic Variant CIBAR1:p.Gln129Pro (chr8-93704964-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_145269.5(CIBAR1):c.386A>C(p.Gln129Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,496 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q129R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CIBAR1
NM_145269.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.15

Publications

0 publications found

Variant links:

Genes affected

CIBAR1 (HGNC:30452): (CBY1 interacting BAR domain containing 1) Enables phospholipid binding activity. Involved in several processes, including inner mitochondrial membrane organization; limb morphogenesis; and membrane tubulation. Located in several cellular components, including centriole; ciliary base; and mitochondrial crista. [provided by Alliance of Genome Resources, Apr 2022]

CIBAR1 Gene-Disease associations (from GenCC):

postaxial polydactyly type A
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
polydactyly, postaxial, type A9
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CIBAR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145269.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIBAR1	NM_145269.5	MANE Select	c.386A>C	p.Gln129Pro	missense	Exon 4 of 9	NP_660312.2	A1XBS5-1
CIBAR1	NM_001283034.2		c.386A>C	p.Gln129Pro	missense	Exon 4 of 8	NP_001269963.1	A1XBS5-2
CIBAR1	NR_104267.2		n.484A>C		non_coding_transcript_exon	Exon 4 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIBAR1	ENST00000518322.6	TSL:5 MANE Select	c.386A>C	p.Gln129Pro	missense	Exon 4 of 9	ENSP00000429367.1	A1XBS5-1
CIBAR1	ENST00000423990.6	TSL:5	c.386A>C	p.Gln129Pro	missense	Exon 4 of 8	ENSP00000401774.2	A1XBS5-2
CIBAR1	ENST00000523453.5	TSL:5	c.416A>C	p.Gln139Pro	missense	Exon 4 of 6	ENSP00000430812.1	H0YC32

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726502

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39622

South Asian (SAS)

AF:

0.00

AC:

AN:

85948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111442

Other (OTH)

AF:

0.0000332

AC:

AN:

60328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.43

PhyloP100

9.1

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.61

Sift

Benign

0.060

Sift4G

Uncertain

0.010

Polyphen

0.85

Vest4

0.86

MutPred

0.61

Loss of helix (P = 0.0104)

MVP

0.83

MPC

0.63

ClinPred

0.99

GERP RS

5.5

Varity_R

0.79

gMVP

0.83

Mutation Taster

=10/90

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over