Genetic Variant HADH:c.419+37_419+39delTTT (chr4-108014612-CTTT-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_005327.7(HADH):c.419+37_419+39delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,123,236 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00010 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HADH
NM_005327.7 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
HADH	NM_005327.7 link	c.419+37_419+39delTTT	intron_variant	Intron 3 of 7	ENST00000309522.8	NP_005318.6
HADH	NM_001184705.4 link	c.419+37_419+39delTTT	intron_variant	Intron 3 of 8		NP_001171634.3
HADH	NM_001331027.2 link	c.431+37_431+39delTTT	intron_variant	Intron 3 of 7		NP_001317956.2
HADH	XR_007096395.1 link	n.463+37_463+39delTTT	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+37_419+39delTTT		intron_variant	Intron 3 of 7	1	NM_005327.7	ENSP00000312288.4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

145876

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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

GnomAD2 exomes

AF:

0.0000655

AC:

AN:

122084

AF XY:

0.0000919

show subpopulations

Gnomad AFR exome

AF:

0.000110

Gnomad AMR exome

AF:

0.0000687

Gnomad ASJ exome

AF:

0.000225

Gnomad EAS exome

AF:

0.000127

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000344

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

114

AN:

1123236

Hom.:

AF XY:

0.000101

AC XY:

AN XY:

563022

show subpopulations

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

African (AFR)

AF:

0.000118

AC:

AN:

25378

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.0000470

AC:

AN:

21254

East Asian (EAS)

AF:

0.00

AC:

AN:

32384

South Asian (SAS)

AF:

0.0000572

AC:

AN:

69890

European-Finnish (FIN)

AF:

0.0000464

AC:

AN:

43072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4712

European-Non Finnish (NFE)

AF:

0.000120

AC:

101

AN:

844422

Other (OTH)

AF:

0.0000639

AC:

AN:

46922

⚠️ 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: 0.252

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

145876

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70794

African (AFR)

AF:

0.00

AC:

AN:

39190

American (AMR)

AF:

0.00

AC:

AN:

14668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.00

AC:

AN:

5040

South Asian (SAS)

AF:

0.00

AC:

AN:

4600

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66348

Other (OTH)

AF:

0.00

AC:

AN:

1988

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=100/0

polymorphism

(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

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4-108014612-CTTTT-CT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over