14-73537803-T-G

Position:

• chr14-73537803-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001037161.2(ACOT1):​c.382T>G​(p.Tyr128Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y128C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 19)
• Consequence: ACOT1 NM_001037161.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.857

Genes affected

ACOT1 (HGNC:33128): (acyl-CoA thioesterase 1) Enables acyl-CoA hydrolase activity. Involved in acyl-CoA metabolic process; long-chain fatty acid metabolic process; and very long-chain 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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052404612).
• BP6: Variant 14-73537803-T-G is Benign according to our data. Variant chr14-73537803-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3137286.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACOT1	NM_001037161.2	c.382T>G	p.Tyr128Asp	missense_variant	1/3	ENST00000311148.9	NP_001032238.1
HEATR4	NM_001220484.1	c.-151-7559A>C		intron_variant		ENST00000553558.6	NP_001207413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACOT1	ENST00000311148.9	c.382T>G	p.Tyr128Asp	missense_variant	1/3	1	NM_001037161.2	ENSP00000311224.4
HEATR4	ENST00000553558.6	c.-151-7559A>C		intron_variant		2	NM_001220484.1	ENSP00000450444.2

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 19

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.2
DANN	Benign	0.44
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.035	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N;.
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.10
Sift	Benign	0.22	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0	B;.
Vest4		0.065
MutPred		0.60		Gain of catalytic residue at P131 (P = 0.0028);Gain of catalytic residue at P131 (P = 0.0028);
MVP		0.37
ClinPred		0.12	T
GERP RS		-4.8
Varity_R		0.053
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-74004507;