3-15567941-C-A

Variant names:

• chr3-15567941-C-A
• rs111333255
• NM_012260.4:c.1312G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_012260.4(HACL1):​c.1312G>T​(p.Val438Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,613,834 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V438M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: HACL1 NM_012260.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -2.52
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067287087).
• BP6: Variant 3-15567941-C-A is Benign according to our data. Variant chr3-15567941-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3055290.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012260.4. 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
	HACL1	NM_012260.4	MANE Select	c.1312G>T	p.Val438Leu	missense	Exon 14 of 17	NP_036392.2	Q9UJ83-1
	HACL1	NM_001284413.2		c.1231G>T	p.Val411Leu	missense	Exon 13 of 16	NP_001271342.1	Q9UJ83-2
	HACL1	NM_001284415.2		c.1132G>T	p.Val378Leu	missense	Exon 12 of 15	NP_001271344.1	Q9UJ83-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HACL1	ENST00000321169.10	TSL:1 MANE Select	c.1312G>T	p.Val438Leu	missense	Exon 14 of 17	ENSP00000323811.5	Q9UJ83-1
	HACL1	ENST00000383779.8	TSL:1	n.*773G>T		non_coding_transcript_exon	Exon 12 of 15	ENSP00000373289.4	Q7Z773
	HACL1	ENST00000383779.8	TSL:1	n.*773G>T		3_prime_UTR	Exon 12 of 15	ENSP00000373289.4	Q7Z773

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00545

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000350 AC: 88 AN: 251358 AF XY: 0.000258

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000147 AC: 215 AN: 1461496 Hom.: 1 Cov.: 31 AF XY: 0.000133 AC XY: 97 AN XY: 727110

African (AFR) AF: 0.00514 AC: 172 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86248

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

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111644

Other (OTH) AF: 0.000364 AC: 22 AN: 60384

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74492

African (AFR) AF: 0.00546 AC: 227 AN: 41572

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000358 Hom.: 0

Bravo AF: 0.00161

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000428 AC: 52

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HACL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.0010
DANN	Benign	0.21
DEOGEN2	Benign	0.17	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-2.5
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.077
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.42		Loss of catalytic residue at V438 (P = 0.0841)
MVP		0.16
MPC		0.085
ClinPred		0.0088	T
GERP RS		-11
Varity_R		0.030
gMVP		0.53
Mutation Taster		=99/1	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: rs111333255; hg19: chr3-15609448;