NM_012260.4:c.1723C>G

Variant names:

• chr3-15560879-G-C
• rs141491413
• NM_012260.4:c.1723C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012260.4(HACL1):​c.1723C>G​(p.Arg575Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R575C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HACL1 NM_012260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.40
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2642371).

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.1723C>G	p.Arg575Gly	missense	Exon 17 of 17	NP_036392.2	Q9UJ83-1
	HACL1	NM_001284413.2		c.1642C>G	p.Arg548Gly	missense	Exon 16 of 16	NP_001271342.1	Q9UJ83-2
	HACL1	NM_001284415.2		c.1543C>G	p.Arg515Gly	missense	Exon 15 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.1723C>G	p.Arg575Gly	missense	Exon 17 of 17	ENSP00000323811.5	Q9UJ83-1
	HACL1	ENST00000383779.8	TSL:1	n.*1184C>G		non_coding_transcript_exon	Exon 15 of 15	ENSP00000373289.4	Q7Z773
	HACL1	ENST00000383779.8	TSL:1	n.*1184C>G		3_prime_UTR	Exon 15 of 15	ENSP00000373289.4	Q7Z773

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249780 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454368 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724076

African (AFR) AF: 0.00 AC: 0 AN: 33278

American (AMR) AF: 0.00 AC: 0 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 85844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1106092

Other (OTH) AF: 0.00 AC: 0 AN: 60108

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	0.0082	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.4
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.025	D
Polyphen		0.70	P
Vest4		0.33
MutPred		0.44		Loss of MoRF binding (P = 2e-04)
MVP		0.68
MPC		0.25
ClinPred		0.98	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.61
gMVP		0.62
Mutation Taster		=57/43	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: rs141491413; hg19: chr3-15602386;