3-15568563-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_012260.4(HACL1):c.1119G>A(p.Leu373=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,551,692 control chromosomes in the GnomAD database, including 11,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (950 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10214 hom.)
• Consequence: HACL1 NM_012260.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.09

Genes affected

HACL1 (HGNC:17856): (2-hydroxyacyl-CoA lyase 1) Enables several functions, including 2-hydroxy-3-methylhexadecanoyl-CoA lyase activity; ATP binding activity; and cation binding activity. Involved in fatty acid alpha-oxidation; phytanic acid metabolic process; and protein targeting to peroxisome. Located in nucleoplasm and peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 3-15568563-C-T is Benign according to our data. Variant chr3-15568563-C-T is described in ClinVar as [Benign]. Clinvar id is 3057081.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HACL1	NM_012260.4	c.1119G>A	p.Leu373=	synonymous_variant	13/17	ENST00000321169.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HACL1	ENST00000321169.10	c.1119G>A	p.Leu373=	synonymous_variant	13/17	1	NM_012260.4	P1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16481 AN: 152046 Hom.: 953 Cov.: 32

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0844

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.115 AC: 26517 AN: 231572 Hom.: 1659 AF XY: 0.118 AC XY: 14758 AN XY: 125166

Gnomad AFR exome AF: 0.0799

Gnomad AMR exome AF: 0.0485

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.143

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.117 AC: 163163 AN: 1399528 Hom.: 10214 Cov.: 24 AF XY: 0.118 AC XY: 82572 AN XY: 697148

Gnomad4 AFR exome AF: 0.0787

Gnomad4 AMR exome AF: 0.0520

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.108 AC: 16484 AN: 152164 Hom.: 950 Cov.: 32 AF XY: 0.110 AC XY: 8157 AN XY: 74374

Gnomad4 AFR AF: 0.0817

Gnomad4 AMR AF: 0.0842

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.112

Alfa AF: 0.114 Hom.: 1546

Bravo AF: 0.102

Asia WGS AF: 0.117 AC: 404 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HACL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	8.8
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs905650; hg19: chr3-15610070; COSMIC: COSV58254617;