3-15563368-C-T

Variant names:

• chr3-15563368-C-T
• rs149555880
• NM_012260.4:c.1694G>A

Variant summary

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

The NM_012260.4(HACL1):​c.1694G>A​(p.Arg565Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,611,716 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R565W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: HACL1 NM_012260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38
• Publications: 4 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 0 ACMG points.

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.1694G>A	p.Arg565Gln	missense	Exon 16 of 17	NP_036392.2	Q9UJ83-1
	HACL1	NM_001284413.2		c.1613G>A	p.Arg538Gln	missense	Exon 15 of 16	NP_001271342.1	Q9UJ83-2
	HACL1	NM_001284415.2		c.1514G>A	p.Arg505Gln	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.1694G>A	p.Arg565Gln	missense	Exon 16 of 17	ENSP00000323811.5	Q9UJ83-1
	HACL1	ENST00000383779.8	TSL:1	n.*1155G>A		non_coding_transcript_exon	Exon 14 of 15	ENSP00000373289.4	Q7Z773
	HACL1	ENST00000383779.8	TSL:1	n.*1155G>A		3_prime_UTR	Exon 14 of 15	ENSP00000373289.4	Q7Z773

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000288 AC: 72 AN: 250328 AF XY: 0.000333

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000592

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000512 AC: 748 AN: 1459640 Hom.: 1 Cov.: 30 AF XY: 0.000492 AC XY: 357 AN XY: 726218

African (AFR) AF: 0.0000299 AC: 1 AN: 33418

American (AMR) AF: 0.0000897 AC: 4 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000638 AC: 708 AN: 1110358

Other (OTH) AF: 0.000564 AC: 34 AN: 60312

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74300

African (AFR) AF: 0.0000724 AC: 3 AN: 41408

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000449 Hom.: 0

Bravo AF: 0.000291

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000600

EpiControl AF: 0.000771

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	Pathogenic	0.60
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.4
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.27
Sift	Benign	0.19	T
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.71
MVP		0.50
MPC		0.41
ClinPred		0.52	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.66
Mutation Taster		=25/75	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: rs149555880; hg19: chr3-15604875;