chr3-15563521-G-C

Variant names:

• chr3-15563521-G-C
• rs999656083
• NM_012260.4:c.1541C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012260.4(HACL1):​c.1541C>G​(p.Pro514Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,890 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P514L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HACL1 NM_012260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.39
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

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.1541C>G	p.Pro514Arg	missense	Exon 16 of 17	NP_036392.2	Q9UJ83-1
	HACL1	NM_001284413.2		c.1460C>G	p.Pro487Arg	missense	Exon 15 of 16	NP_001271342.1	Q9UJ83-2
	HACL1	NM_001284415.2		c.1361C>G	p.Pro454Arg	missense	Exon 14 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.1541C>G	p.Pro514Arg	missense	Exon 16 of 17	ENSP00000323811.5	Q9UJ83-1
	HACL1	ENST00000383779.8	TSL:1	n.*1002C>G		non_coding_transcript_exon	Exon 14 of 15	ENSP00000373289.4	Q7Z773
	HACL1	ENST00000383779.8	TSL:1	n.*1002C>G		3_prime_UTR	Exon 14 of 15	ENSP00000373289.4	Q7Z773

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457890 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725480

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108698

Other (OTH) AF: 0.00 AC: 0 AN: 60258

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.61
Sift	Benign	0.31	T
Sift4G	Benign	0.27	T
Polyphen		1.0	D
Vest4		0.92
MutPred		0.53		Gain of glycosylation at Y518 (P = 0.0065)
MVP		0.83
MPC		0.45
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.43
gMVP		0.80
Mutation Taster		=29/71	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: rs999656083; hg19: chr3-15605028;