Genetic Variant HADH:c.419+38_419+39delTT (chr4-108014612-CTT-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_005327.7(HADH):c.419+38_419+39delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,238,718 control chromosomes in the GnomAD database, including 6 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0025 ( 6 hom. )

Consequence

HADH
NM_005327.7 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.11

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0025 (2737/1092856) while in subpopulation AFR AF = 0.0043 (106/24648). AF 95% confidence interval is 0.00364. There are 6 homozygotes in GnomAdExome4. There are 1213 alleles in the male GnomAdExome4 subpopulation. This position FAILED quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HADH	NM_005327.7 link	c.419+38_419+39delTT	intron_variant	Intron 3 of 7	ENST00000309522.8	NP_005318.6	Q16836-1A0A140VK76
HADH	NM_001184705.4 link	c.419+38_419+39delTT	intron_variant	Intron 3 of 8		NP_001171634.3	Q16836-3
HADH	NM_001331027.2 link	c.431+38_431+39delTT	intron_variant	Intron 3 of 7		NP_001317956.2	B3KTT6
HADH	XR_007096395.1 link	n.463+38_463+39delTT	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+25_419+26delTT		intron_variant	Intron 3 of 7	1	NM_005327.7	ENSP00000312288.4		Q16836-1

Frequencies

GnomAD3 genomes

AF:

0.0000274

AC:

AN:

145798

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000255

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:

0.000213

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00169

AC:

206

AN:

122084

AF XY:

0.00165

show subpopulations

Gnomad AFR exome

AF:

0.000660

Gnomad AMR exome

AF:

0.00254

Gnomad ASJ exome

AF:

0.00180

Gnomad EAS exome

AF:

0.00152

Gnomad FIN exome

AF:

0.00169

Gnomad NFE exome

AF:

0.00158

Gnomad OTH exome

AF:

0.00394

GnomAD4 exome

AF:

0.00250

AC:

2737

AN:

1092856

Hom.:

AF XY:

0.00221

AC XY:

1213

AN XY:

548252

show subpopulations

Gnomad4 AFR exome

AF:

0.00430

AC:

106

AN:

24648

Gnomad4 AMR exome

AF:

0.00156

AC:

AN:

34658

Gnomad4 ASJ exome

AF:

0.00130

AC:

AN:

20782

Gnomad4 EAS exome

AF:

0.000727

AC:

AN:

31630

Gnomad4 SAS exome

AF:

0.00113

AC:

AN:

68914

Gnomad4 FIN exome

AF:

0.00145

AC:

AN:

42152

Gnomad4 NFE exome

AF:

0.00279

AC:

2288

AN:

819810

Gnomad4 Remaining exome

AF:

0.00212

AC:

AN:

45648

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

Heterozygous variant carriers

415

831

1246

1662

2077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

116

232

348

464

580

<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:

0.0000274

AC:

AN:

145862

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

70830

show subpopulations

Gnomad4 AFR

AF:

0.0000255

AC:

0.0000254686

AN:

0.0000254686

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.000213

AC:

0.000212993

AN:

0.000212993

Gnomad4 NFE

AF:

0.0000151

AC:

0.0000150816

AN:

0.0000150816

Gnomad4 OTH

AF:

0.00

AC:

AN:

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

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.00245

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=100/0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

4-108014612-CTTTT-CTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over