4-108009883-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005327.7(HADH):c.257T>C(p.Leu86Pro) variant causes a missense change. The variant allele was found at a frequency of 0.914 in 1,607,364 control chromosomes in the GnomAD database, including 674,453 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.87 ( 57994 hom., cov: 29)

Exomes 𝑓: 0.92 ( 616459 hom. )

Consequence

HADH
NM_005327.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.211664E-7).

BP6

Variant 4-108009883-T-C is Benign according to our data. Variant chr4-108009883-T-C is described in ClinVar as Benign. ClinVar VariationId is 167162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HADH	NM_005327.7 link	c.257T>C	p.Leu86Pro	missense_variant	Exon 2 of 8	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4 link	c.257T>C	p.Leu86Pro	missense_variant	Exon 2 of 9		NP_001171634.3
HADH	NM_001331027.2 link	c.269T>C	p.Leu90Pro	missense_variant	Exon 2 of 8		NP_001317956.2
HADH	XR_007096395.1 link	n.301T>C		non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8 link	c.257T>C	p.Leu86Pro	missense_variant	Exon 2 of 8	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes

AF:

0.867

AC:

131686

AN:

151928

Hom.:

57953

Cov.:

show subpopulations

Gnomad AFR

AF:

0.696

Gnomad AMI

AF:

0.946

Gnomad AMR

AF:

0.931

Gnomad ASJ

AF:

0.975

Gnomad EAS

AF:

0.972

Gnomad SAS

AF:

0.902

Gnomad FIN

AF:

0.963

Gnomad MID

AF:

0.943

Gnomad NFE

AF:

0.923

Gnomad OTH

AF:

0.893

GnomAD2 exomes

AF:

0.921

AC:

231638

AN:

251446

AF XY:

0.921

show subpopulations

Gnomad AFR exome

AF:

0.695

Gnomad AMR exome

AF:

0.963

Gnomad ASJ exome

AF:

0.975

Gnomad EAS exome

AF:

0.975

Gnomad FIN exome

AF:

0.961

Gnomad NFE exome

AF:

0.926

Gnomad OTH exome

AF:

0.931

GnomAD4 exome

AF:

0.919

AC:

1338010

AN:

1455316

Hom.:

616459

Cov.:

AF XY:

0.919

AC XY:

665677

AN XY:

724400

show subpopulations

African (AFR)

AF:

0.694

AC:

23133

AN:

33338

American (AMR)

AF:

0.959

AC:

42881

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.975

AC:

25437

AN:

26088

East Asian (EAS)

AF:

0.968

AC:

38413

AN:

39676

South Asian (SAS)

AF:

0.896

AC:

77170

AN:

86118

European-Finnish (FIN)

AF:

0.960

AC:

51250

AN:

53410

Middle Eastern (MID)

AF:

0.910

AC:

5241

AN:

5758

European-Non Finnish (NFE)

AF:

0.921

AC:

1019211

AN:

1106048

Other (OTH)

AF:

0.919

AC:

55274

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

4760

9520

14280

19040

23800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21356

42712

64068

85424

106780

<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:

0.867

AC:

131787

AN:

152048

Hom.:

57994

Cov.:

AF XY:

0.871

AC XY:

64705

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.697

AC:

28852

AN:

41408

American (AMR)

AF:

0.931

AC:

14239

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.975

AC:

3385

AN:

3472

East Asian (EAS)

AF:

0.972

AC:

5021

AN:

5166

South Asian (SAS)

AF:

0.902

AC:

4348

AN:

4820

European-Finnish (FIN)

AF:

0.963

AC:

10181

AN:

10574

Middle Eastern (MID)

AF:

0.942

AC:

277

AN:

294

European-Non Finnish (NFE)

AF:

0.923

AC:

62735

AN:

68004

Other (OTH)

AF:

0.894

AC:

1886

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

795

1590

2385

3180

3975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

892

1784

2676

3568

4460

<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:

0.910

Hom.:

276794

Bravo

AF:

0.859

TwinsUK

AF:

0.916

AC:

3398

ALSPAC

AF:

0.920

AC:

3546

ESP6500AA

AF:

0.704

AC:

3104

ESP6500EA

AF:

0.924

AC:

7944

ExAC

AF:

0.915

AC:

111095

Asia WGS

AF:

0.923

AC:

3211

AN:

3478

EpiCase

AF:

0.926

EpiControl

AF:

0.928

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

May 16, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of 3-hydroxyacyl-CoA dehydrogenase

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.039

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.13

.;.;T;.;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.12

T;T;T;T;T

MetaRNN

Benign

7.2e-7

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.0

.;N;N;.;.

PhyloP100

4.9

PrimateAI

Benign

0.48

PROVEAN

Benign

5.9

.;.;N;N;.

REVEL

Benign

0.27

Sift

Benign

1.0

.;.;T;T;.

Sift4G

Benign

0.71

.;T;T;.;T

Polyphen

0.0

.;.;B;.;.

Vest4

0.050, 0.047, 0.074

MPC

0.38

ClinPred

0.0075

GERP RS

4.3

Varity_R

0.19

gMVP

0.54

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over