NM_145269.5:c.394_397delAGAA

Variant names:

• chr8-93704967-TAGAA-T
• rs762464497
• NM_145269.5:c.394_397delAGAA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_145269.5(CIBAR1):​c.394_397delAGAA​(p.Arg132HisfsTer45) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,584 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CIBAR1 NM_145269.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.15
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-93704967-TAGAA-T is Pathogenic according to our data. Variant chr8-93704967-TAGAA-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2442170.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIBAR1	NM_145269.5	MANE Select	c.394_397delAGAA	p.Arg132HisfsTer45	frameshift	Exon 4 of 9	NP_660312.2	A1XBS5-1
	CIBAR1	NM_001283034.2		c.394_397delAGAA	p.Arg132HisfsTer45	frameshift	Exon 4 of 8	NP_001269963.1	A1XBS5-2
	CIBAR1	NR_104267.2		n.492_495delAGAA		non_coding_transcript_exon	Exon 4 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIBAR1	ENST00000518322.6	TSL:5 MANE Select	c.394_397delAGAA	p.Arg132HisfsTer45	frameshift	Exon 4 of 9	ENSP00000429367.1	A1XBS5-1
	CIBAR1	ENST00000423990.6	TSL:5	c.394_397delAGAA	p.Arg132HisfsTer45	frameshift	Exon 4 of 8	ENSP00000401774.2	A1XBS5-2
	CIBAR1	ENST00000523453.5	TSL:5	c.424_427delAGAA	p.Arg142fs	frameshift	Exon 4 of 6	ENSP00000430812.1	H0YC32

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248368 AF XY: 0.0000223

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460584 Hom.: 0 AF XY: 0.00000826 AC XY: 6 AN XY: 726552

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111446

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Polydactyly, postaxial, type A9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=10/190	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs762464497; hg19: chr8-94717195;