3-128910144-C-G

Variant names:

• chr3-128910144-C-G
• rs1057518752
• NM_014049.5:c.1687C>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_014049.5(ACAD9):​c.1687C>G​(p.His563Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACAD9 NM_014049.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.86

Genes affected

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852
• PP5: Variant 3-128910144-C-G is Pathogenic according to our data. Variant chr3-128910144-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 372250.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAD9	NM_014049.5	c.1687C>G	p.His563Asp	missense_variant	Exon 16 of 18	ENST00000308982.12	NP_054768.2
CFAP92	NM_001394090.1	c.*155G>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000645291.3	NP_001381019.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAD9	ENST00000308982.12	c.1687C>G	p.His563Asp	missense_variant	Exon 16 of 18	1	NM_014049.5	ENSP00000312618.7
CFAP92	ENST00000645291	c.*155G>C		3_prime_UTR_variant	Exon 16 of 16		NM_001394090.1	ENSP00000496592.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461692 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acyl-CoA dehydrogenase 9 deficiency Pathogenic:1

Dec 13, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.78
MutPred		0.52		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.96
MPC		0.72
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs1057518752; hg19: chr3-128628987;