3-38136908-C-T

Variant names:

• chr3-38136908-C-T
• rs1302822146
• NM_001607.4:c.128G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001607.4(ACAA1):​c.128G>A​(p.Gly43Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ACAA1 NM_001607.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15
• Publications: 0 publications found

Genes affected

ACAA1 (HGNC:82): (acetyl-CoA acyltransferase 1) This gene encodes an enzyme operative in the beta-oxidation system of the peroxisomes. Deficiency of this enzyme leads to pseudo-Zellweger syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001607.4. 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
	ACAA1	NM_001607.4	MANE Select	c.128G>A	p.Gly43Glu	missense	Exon 1 of 12	NP_001598.1	P09110-1
	ACAA1	NM_001130410.2		c.128G>A	p.Gly43Glu	missense	Exon 1 of 10	NP_001123882.1	P09110-2
	ACAA1	NR_024024.2		n.220G>A		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAA1	ENST00000333167.13	TSL:1 MANE Select	c.128G>A	p.Gly43Glu	missense	Exon 1 of 12	ENSP00000333664.8	P09110-1
	ACAA1	ENST00000301810.11	TSL:1	c.128G>A	p.Gly43Glu	missense	Exon 1 of 10	ENSP00000301810.7	P09110-2
	ACAA1	ENST00000411549.5	TSL:1	n.128G>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000414021.1	B4DVF4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383320 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 682570

African (AFR) AF: 0.00 AC: 0 AN: 30620

American (AMR) AF: 0.00 AC: 0 AN: 35316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24894

East Asian (EAS) AF: 0.00 AC: 0 AN: 35104

South Asian (SAS) AF: 0.00 AC: 0 AN: 78904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4288

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076556

Other (OTH) AF: 0.00 AC: 0 AN: 57534

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.2
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.79		Loss of MoRF binding (P = 0.0312)
MVP		0.94
MPC		1.3
ClinPred		0.98	D
GERP RS		5.4
PromoterAI		0.0044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97
Mutation Taster		=10/90	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: rs1302822146; hg19: chr3-38178399;