dbSNP rs751225330: HACL1:p.Phe423Ser (chr3-15567985-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_012260.4(HACL1):c.1268T>C(p.Phe423Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

HACL1
NM_012260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.04

Publications

2 publications found

Variant links:

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]

HACL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 0.909

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HACL1	NM_012260.4	MANE Select	c.1268T>C	p.Phe423Ser	missense	Exon 14 of 17	NP_036392.2	Q9UJ83-1
HACL1	NM_001284413.2		c.1187T>C	p.Phe396Ser	missense	Exon 13 of 16	NP_001271342.1	Q9UJ83-2
HACL1	NM_001284415.2		c.1088T>C	p.Phe363Ser	missense	Exon 12 of 15	NP_001271344.1	Q9UJ83-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HACL1	ENST00000321169.10	TSL:1 MANE Select	c.1268T>C	p.Phe423Ser	missense	Exon 14 of 17	ENSP00000323811.5	Q9UJ83-1
HACL1	ENST00000383779.8	TSL:1	n.*729T>C		non_coding_transcript_exon	Exon 12 of 15	ENSP00000373289.4	Q7Z773
HACL1	ENST00000383779.8	TSL:1	n.*729T>C		3_prime_UTR	Exon 12 of 15	ENSP00000373289.4	Q7Z773

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251272

AF XY:

0.0000147

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.049

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.1

PhyloP100

5.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.3

REVEL

Uncertain

0.53

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.033

Polyphen

0.98

Vest4

0.89

MutPred

0.79

Gain of disorder (P = 5e-04)

MVP

0.71

MPC

0.33

ClinPred

0.97

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.68

gMVP

0.93

Mutation Taster

=10/90

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over