4-108014612-CTTTT-CTTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_005327.7(HADH):c.419+39delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 145,440 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.23 ( 165 hom. )

Failed GnomAD Quality Control

Consequence

HADH
NM_005327.7 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.11

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 4-108014612-CT-C is Benign according to our data. Variant chr4-108014612-CT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435392.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
HADH	NM_005327.7 link	c.419+39delT	intron_variant	Intron 3 of 7	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4 link	c.419+39delT	intron_variant	Intron 3 of 8		NP_001171634.3
HADH	NM_001331027.2 link	c.431+39delT	intron_variant	Intron 3 of 7		NP_001317956.2
HADH	XR_007096395.1 link	n.463+39delT	intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADH	ENST00000309522.8 link	c.419+39delT		intron_variant	Intron 3 of 7	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes

AF:

0.00316

AC:

459

AN:

145380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00209

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00253

Gnomad ASJ

AF:

0.00117

Gnomad EAS

AF:

0.00139

Gnomad SAS

AF:

0.00413

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00312

Gnomad OTH

AF:

0.00101

GnomAD2 exomes

AF:

0.259

AC:

31566

AN:

122084

AF XY:

0.268

show subpopulations

Gnomad AFR exome

AF:

0.232

Gnomad AMR exome

AF:

0.302

Gnomad ASJ exome

AF:

0.352

Gnomad EAS exome

AF:

0.227

Gnomad FIN exome

AF:

0.228

Gnomad NFE exome

AF:

0.236

Gnomad OTH exome

AF:

0.267

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.231

AC:

190128

AN:

824632

Hom.:

165

Cov.:

AF XY:

0.238

AC XY:

95865

AN XY:

403542

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.246

AC:

4778

AN:

19434

American (AMR)

AF:

0.261

AC:

6019

AN:

23104

Ashkenazi Jewish (ASJ)

AF:

0.302

AC:

3968

AN:

13138

East Asian (EAS)

AF:

0.291

AC:

5479

AN:

18810

South Asian (SAS)

AF:

0.297

AC:

11490

AN:

38672

European-Finnish (FIN)

AF:

0.267

AC:

7752

AN:

28996

Middle Eastern (MID)

AF:

0.158

AC:

575

AN:

3634

European-Non Finnish (NFE)

AF:

0.220

AC:

141864

AN:

645794

Other (OTH)

AF:

0.248

AC:

8203

AN:

33050

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.266

Heterozygous variant carriers

21178

42356

63534

84712

105890

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5076

10152

15228

20304

25380

<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:

0.00316

AC:

460

AN:

145440

Hom.:

Cov.:

AF XY:

0.00341

AC XY:

241

AN XY:

70618

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00209

AC:

AN:

39234

American (AMR)

AF:

0.00253

AC:

AN:

14640

Ashkenazi Jewish (ASJ)

AF:

0.00117

AC:

AN:

3414

East Asian (EAS)

AF:

0.00139

AC:

AN:

5022

South Asian (SAS)

AF:

0.00436

AC:

AN:

4588

European-Finnish (FIN)

AF:

0.0110

AC:

102

AN:

9242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00312

AC:

206

AN:

66116

Other (OTH)

AF:

0.00100

AC:

AN:

2000

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.324

Heterozygous variant carriers

129

172

215

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:

0.114

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperinsulinemic hypoglycemia

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Potent mutations in HADH gene are associated with congenital hyperinsulinism, which leads to recurrent hypoglycemia. The condition is exacerbated by stress, fasting or excessive dietary protein. May respond well to diazoxide. However, the role of this particular variant rs550348868 in congenital hyperinsulinism is yet to be ascertained.

not specified

Benign:1

Apr 29, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=100/0

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