chr3-15567878-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_012260.4(HACL1):ā€‹c.1375G>Cā€‹(p.Gly459Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000079 ( 0 hom., cov: 32)
Exomes š‘“: 0.00019 ( 1 hom. )

Consequence

HACL1
NM_012260.4 missense

Scores

11
4
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.95
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HACL1NM_012260.4 linkuse as main transcriptc.1375G>C p.Gly459Arg missense_variant 14/17 ENST00000321169.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HACL1ENST00000321169.10 linkuse as main transcriptc.1375G>C p.Gly459Arg missense_variant 14/171 NM_012260.4 P1Q9UJ83-1

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000994
AC:
25
AN:
251414
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135868
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000220
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000187
AC:
274
AN:
1461780
Hom.:
1
Cov.:
31
AF XY:
0.000187
AC XY:
136
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000246
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000789
AC:
12
AN:
152156
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000120
Hom.:
0
Bravo
AF:
0.0000831
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 14, 2023The c.1375G>C (p.G459R) alteration is located in exon 14 (coding exon 14) of the HACL1 gene. This alteration results from a G to C substitution at nucleotide position 1375, causing the glycine (G) at amino acid position 459 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Uncertain
0.049
T
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.37
T;.;.;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D
M_CAP
Benign
0.051
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D
MetaSVM
Benign
-0.45
T
MutationAssessor
Uncertain
2.7
M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-7.9
D;D;D;D;D
REVEL
Uncertain
0.54
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;D;.;.;.
Vest4
0.94
MutPred
0.80
Loss of glycosylation at S461 (P = 0.004);.;.;.;.;
MVP
0.79
MPC
0.52
ClinPred
0.96
D
GERP RS
5.5
Varity_R
0.91
gMVP
0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs145006644; hg19: chr3-15609385; API