3-128910014-ATCCCAGACCATC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_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. 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.98
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 0.06913184 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.
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 rank MANE Protein UniProt
CFAP92NM_001394090.1 linkc.*273_*284delGATGGTCTGGGA 3_prime_UTR_variant Exon 16 of 16 ENST00000645291.3 NP_001381019.1
ACAD9NM_014049.5 linkc.1564-6_1569delTCCCAGACCATC p.Thr522_Met524del splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant Exon 16 of 18 ENST00000308982.12 NP_054768.2 Q9H845

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFAP92ENST00000645291 linkc.*273_*284delGATGGTCTGGGA 3_prime_UTR_variant Exon 16 of 16 NM_001394090.1 ENSP00000496592.2 A0A2R8YFM9
ACAD9ENST00000308982.12 linkc.1564-6_1569delTCCCAGACCATC p.Thr522_Met524del splice_acceptor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant Exon 16 of 18 1 NM_014049.5 ENSP00000312618.7 Q9H845

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
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Sep 08, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 242460). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs863225059; hg19: chr3-128628857; API