14-73619405-G-C

Variant names:

• chr14-73619405-G-C
• rs1890593127
• NM_001365788.1:c.832G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365788.1(ACOT6):​c.832G>C​(p.Asp278His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACOT6 NM_001365788.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.918
• Publications: 0 publications found

Genes affected

ACOT6 (HGNC:33159): (acyl-CoA thioesterase 6) Predicted to enable acyl-CoA hydrolase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid metabolic process. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

HEATR4 (HGNC:16761): (HEAT repeat containing 4) Predicted to enable oxidoreductase activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000258603 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31726232).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365788.1. 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
	ACOT6	NM_001365788.1	MANE Select	c.832G>C	p.Asp278His	missense	Exon 3 of 3	NP_001352717.1	Q3I5F7-1
	ACOT6	NM_001037162.1		c.190G>C	p.Asp64His	missense	Exon 2 of 2	NP_001032239.1	Q3I5F7-2
	ACOT6	NM_001365789.1		c.190G>C	p.Asp64His	missense	Exon 4 of 4	NP_001352718.1	Q3I5F7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACOT6	ENST00000645972.2	MANE Select	c.832G>C	p.Asp278His	missense	Exon 3 of 3	ENSP00000496277.1	Q3I5F7-1
	ACOT6	ENST00000381139.1	TSL:1	c.190G>C	p.Asp64His	missense	Exon 2 of 2	ENSP00000370531.1	Q3I5F7-2
	ACOT6	ENST00000554229.1	TSL:3	c.190G>C	p.Asp64His	missense	Exon 4 of 4	ENSP00000451464.1	G3V3W6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.051
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.92
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.081
Sift	Benign	0.047	D
Sift4G	Benign	0.067	T
Polyphen		0.81	P
Vest4		0.15
MutPred		0.52		Gain of methylation at K69 (P = 0.1087)
MVP		0.12
MPC		0.43
ClinPred		0.79	D
GERP RS		3.9
Varity_R		0.22
gMVP		0.60
Mutation Taster		=82/18	polymorphism

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: rs1890593127; hg19: chr14-74086109; COSMIC: COSV66969054; COSMIC: COSV66969054;