Genetic Variant HADH:p.Leu86Arg (chr4-108009883-T-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005327.7(HADH):c.257T>G(p.Leu86Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,962 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. L86P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)

Consequence

HADH
NM_005327.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.87

Publications

47 publications found

Variant links:

Genes affected

HADH (HGNC:4799): (hydroxyacyl-CoA dehydrogenase) This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its enzymatic activity is highest with medium-chain-length fatty acids. Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia. The human genome contains a related pseudogene of this gene on chromosome 15. [provided by RefSeq, May 2010]

HADH Gene-Disease associations (from GenCC):

3-hydroxyacyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, ClinGen
hyperinsulinemic hypoglycemia, familial, 4
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

HADH links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005327.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HADH	NM_005327.7	MANE Select	c.257T>G	p.Leu86Arg	missense	Exon 2 of 8	NP_005318.6
HADH	NM_001184705.4		c.257T>G	p.Leu86Arg	missense	Exon 2 of 9	NP_001171634.3
HADH	NM_001331027.2		c.269T>G	p.Leu90Arg	missense	Exon 2 of 8	NP_001317956.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HADH	ENST00000309522.8	TSL:1 MANE Select	c.257T>G	p.Leu86Arg	missense	Exon 2 of 8	ENSP00000312288.4
HADH	ENST00000505878.4	TSL:1	c.434T>G	p.Leu145Arg	missense	Exon 2 of 9	ENSP00000425952.2
HADH	ENST00000603302.5	TSL:1	c.257T>G	p.Leu86Arg	missense	Exon 2 of 9	ENSP00000474560.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151962

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74208

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41310

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

276794

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

0.0076

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

M_CAP

Benign

0.067

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.050

PhyloP100

4.9

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.74

REVEL

Benign

0.26

Sift

Benign

0.042

Sift4G

Benign

0.47

Polyphen

0.0020

Vest4

0.21

MutPred

0.45

Gain of solvent accessibility (P = 0.0018)

MVP

0.78

MPC

0.38

ClinPred

0.79

GERP RS

4.3

Varity_R

0.21

gMVP

0.52

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over