3-128910014-ATCCCAGACCATC-A

Position:

• chr3-128910014-ATCCCAGACCATC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_014049.5(ACAD9):​c.1564-6_1569del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06859592 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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-128910014-ATCCCAGACCATC-A is Pathogenic according to our data. Variant chr3-128910014-ATCCCAGACCATC-A is described in ClinVar as [Pathogenic]. Clinvar id is 242460.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP92	NM_001394090.1	c.*273_*284del		3_prime_UTR_variant	16/16	ENST00000645291.3	NP_001381019.1
ACAD9	NM_014049.5	c.1564-6_1569del		splice_acceptor_variant, coding_sequence_variant, intron_variant	16/18	ENST00000308982.12	NP_054768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP92	ENST00000645291.3	c.*273_*284del		3_prime_UTR_variant	16/16		NM_001394090.1	ENSP00000496592	P2
ACAD9	ENST00000308982.12	c.1564-6_1569del		splice_acceptor_variant, coding_sequence_variant, intron_variant	16/18	1	NM_014049.5	ENSP00000312618	P1

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2023

This variant results in the deletion of part of exon 16 (c.1564-6_1569del) of the ACAD9 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACAD9 are known to be pathogenic (PMID: 25721401). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of mitochondrial complex I deficiency (PMID: 26669660, 30025539). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 242460). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs863225059; hg19: chr3-128628857;