Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000183.3(HADHB):c.966G>A(p.Ala322Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,612,874 control chromosomes in the GnomAD database, including 173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 90 hom., cov: 31)

Exomes 𝑓: 0.0020 ( 83 hom. )

Consequence

HADHB
NM_000183.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.607

Publications

2 publications found

Variant links:

Genes affected

HADHB (HGNC:4803): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta) This gene encodes the beta subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the beta subunit catalyzing the 3-ketoacyl-CoA thiolase activity. The encoded protein can also bind RNA and decreases the stability of some mRNAs. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. Mutations in this gene result in trifunctional protein deficiency. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

HADHB Gene-Disease associations (from GenCC):

mitochondrial trifunctional protein deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, ClinGen

HADHB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 2-26282877-G-A is Benign according to our data. Variant chr2-26282877-G-A is described in ClinVar as Benign. ClinVar VariationId is 137532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.607 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.063 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000183.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HADHB	NM_000183.3	MANE Select	c.966G>A	p.Ala322Ala	synonymous	Exon 11 of 16	NP_000174.1
HADHB	NM_001281512.2		c.921G>A	p.Ala307Ala	synonymous	Exon 10 of 15	NP_001268441.1
HADHB	NM_001281513.2		c.900G>A	p.Ala300Ala	synonymous	Exon 12 of 17	NP_001268442.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HADHB	ENST00000317799.10	TSL:1 MANE Select	c.966G>A	p.Ala322Ala	synonymous	Exon 11 of 16	ENSP00000325136.5
HADHB	ENST00000537713.5	TSL:2	c.921G>A	p.Ala307Ala	synonymous	Exon 10 of 15	ENSP00000444295.1
HADHB	ENST00000545822.2	TSL:5	c.900G>A	p.Ala300Ala	synonymous	Exon 9 of 14	ENSP00000442665.1

Frequencies

GnomAD3 genomes

AF:

0.0190

AC:

2894

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00511

AC:

1285

AN:

251402

AF XY:

0.00379

show subpopulations

Gnomad AFR exome

AF:

0.0662

Gnomad AMR exome

AF:

0.00390

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000510

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00204

AC:

2985

AN:

1460578

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

1321

AN XY:

726700

show subpopulations

African (AFR)

AF:

0.0659

AC:

2204

AN:

33430

American (AMR)

AF:

0.00438

AC:

196

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00590

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

0.000264

AC:

293

AN:

1111036

Other (OTH)

AF:

0.00416

AC:

251

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

149

297

446

594

743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0190

AC:

2895

AN:

152296

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1335

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0650

AC:

2702

AN:

41562

American (AMR)

AF:

0.00790

AC:

121

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68024

Other (OTH)

AF:

0.0133

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

149

297

446

594

743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.00926

Hom.:

Bravo

AF:

0.0220

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mitochondrial trifunctional protein deficiency (2)

Mitochondrial trifunctional protein deficiency 2 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.4

(source)

DANN

Benign

0.68

PhyloP100

-0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over