3-123502648-T-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_198402.5(HACD2):​c.415A>G​(p.Ile139Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,605,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

HACD2
NM_198402.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.21

Publications

0 publications found
Variant links:
Genes affected
HACD2 (HGNC:9640): (3-hydroxyacyl-CoA dehydratase 2) The protein encoded by this gene can catalyze the third step (dehydration) in the conversion of long chain fatty acids to very long chain fatty acids. The encoded protein localizes to the endoplasmic reticulum membrane. [provided by RefSeq, Jul 2016]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011601061).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HACD2NM_198402.5 linkc.415A>G p.Ile139Val missense_variant Exon 5 of 7 ENST00000383657.10 NP_940684.1 Q6Y1H2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HACD2ENST00000383657.10 linkc.415A>G p.Ile139Val missense_variant Exon 5 of 7 1 NM_198402.5 ENSP00000373153.5 Q6Y1H2
HACD2ENST00000469317.1 linkc.82A>G p.Ile28Val missense_variant Exon 5 of 6 3 ENSP00000419237.1 C9JWG1
HACD2ENST00000480081.1 linkn.259A>G non_coding_transcript_exon_variant Exon 1 of 3 4

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
151902
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000509
AC:
12
AN:
235970
AF XY:
0.0000471
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000304
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000343
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1453862
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
10
AN XY:
722194
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33400
American (AMR)
AF:
0.000391
AC:
17
AN:
43498
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25892
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39612
South Asian (SAS)
AF:
0.0000119
AC:
1
AN:
84282
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53034
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1108190
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60186
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.435
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000329
AC:
5
AN:
152018
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74276
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41442
American (AMR)
AF:
0.000327
AC:
5
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4812
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10536
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67998
Other (OTH)
AF:
0.00
AC:
0
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.0000793
ExAC
AF:
0.0000497
AC:
6

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 02, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.415A>G (p.I139V) alteration is located in exon 5 (coding exon 5) of the HACD2 gene. This alteration results from a A to G substitution at nucleotide position 415, causing the isoleucine (I) at amino acid position 139 to be replaced by a valine (V). 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
Benign
0.076
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
11
DANN
Benign
0.59
DEOGEN2
Benign
0.011
T;T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.36
N
LIST_S2
Benign
0.54
T;T
M_CAP
Benign
0.0024
T
MetaRNN
Benign
0.012
T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-0.55
N;.
PhyloP100
1.2
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
0.22
N;N
REVEL
Benign
0.044
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;.
Polyphen
0.0
B;.
Vest4
0.14
MVP
0.043
MPC
0.55
ClinPred
0.021
T
GERP RS
1.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.028
gMVP
0.23
Mutation Taster
=99/1
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

Publications

Other links and lift over

dbSNP: rs187536577; hg19: chr3-123221495; API