3-128910144-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_014049.5(ACAD9):​c.1687C>T​(p.His563Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H563D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACAD9 NM_014049.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-128910144-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 372250.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

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
	ACAD9	NM_014049.5	MANE Select	c.1687C>T	p.His563Tyr	missense	Exon 16 of 18	NP_054768.2
	CFAP92	NM_001394090.1	MANE Select	c.*155G>A		3_prime_UTR	Exon 16 of 16	NP_001381019.1
	ACAD9	NM_001410805.1		c.1318C>T	p.His440Tyr	missense	Exon 15 of 17	NP_001397734.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD9	ENST00000308982.12	TSL:1 MANE Select	c.1687C>T	p.His563Tyr	missense	Exon 16 of 18	ENSP00000312618.7
	CFAP92	ENST00000645291.3	MANE Select	c.*155G>A		3_prime_UTR	Exon 16 of 16	ENSP00000496592.2
	ACAD9	ENST00000511526.5	TSL:1	n.1220C>T		non_coding_transcript_exon	Exon 12 of 14

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.9
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.023	D
Sift4G	Benign	0.073	T
Polyphen		0.99	D
Vest4		0.72
MutPred		0.48		Loss of helix (P = 0.0237)
MVP		0.94
MPC		0.73
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.61
gMVP		0.91
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs1057518752; hg19: chr3-128628987;