3-128910014-ATCCCAGACCATC-A

Variant names:

• chr3-128910014-ATCCCAGACCATC-A
• rs863225059
• NM_001394090.1:c.*273_*284delGATGGTCTGGGA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_014049.5(ACAD9):​c.1564-6_1569delTCCCAGACCATC​(p.Thr522_Met524del) variant causes a splice acceptor, conservative inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACAD9 NM_014049.5 splice_acceptor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.98
• Publications: 0 publications found

Genes affected

CFAP92 (HGNC:29231): (cilia and flagella associated protein 92 (putative))

ACAD9 (HGNC:21497): (acyl-CoA dehydrogenase family member 9) This gene encodes a member of the acyl-CoA dehydrogenase family. Members of this family of proteins localize to the mitochondria and catalyze the rate-limiting step in the beta-oxidation of fatty acyl-CoA. The encoded protein is specifically active toward palmitoyl-CoA and long-chain unsaturated substrates. Mutations in this gene cause acyl-CoA dehydrogenase family member type 9 deficiency. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

ACAD9 Gene-Disease associations (from GenCC):

• acyl-CoA dehydrogenase 9 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06913184 fraction of the gene. Cryptic splice site detected, with MaxEntScore 2.6, offset of -36, new splice context is: catgtgggggactggtctAGgta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 3-128910014-ATCCCAGACCATC-A is Pathogenic according to our data. Variant chr3-128910014-ATCCCAGACCATC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 242460.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014049.5. 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
	CFAP92	NM_001394090.1	MANE Select	c.*273_*284delGATGGTCTGGGA		3_prime_UTR	Exon 16 of 16	NP_001381019.1	A0A2R8YFM9
	ACAD9	NM_014049.5	MANE Select	c.1564-6_1569delTCCCAGACCATC	p.Thr522_Met524del	splice_acceptor conservative_inframe_deletion splice_region intron	Exon 16 of 18	NP_054768.2
	CFAP92	NM_001348520.2		c.*273_*284delGATGGTCTGGGA		3_prime_UTR	Exon 15 of 15	NP_001335449.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP92	ENST00000645291.3	MANE Select	c.*273_*284delGATGGTCTGGGA		3_prime_UTR	Exon 16 of 16	ENSP00000496592.2	A0A2R8YFM9
	ACAD9	ENST00000308982.12	TSL:1 MANE Select	c.1564-6_1569delTCCCAGACCATC	p.Thr522_Met524del	splice_acceptor conservative_inframe_deletion splice_region intron	Exon 16 of 18	ENSP00000312618.7	Q9H845
	ACAD9	ENST00000511526.5	TSL:1	n.1097-6_1102delTCCCAGACCATC		splice_acceptor splice_region intron non_coding_transcript_exon	Exon 12 of 14

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=12/188	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs863225059; hg19: chr3-128628857;