NM_000183.3:c.812-5A>T

Variant names:

• chr2-26279989-A-T
• rs72851534
• NM_000183.3:c.812-5A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000183.3(HADHB):​c.812-5A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,605,282 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (9 hom.)
• Consequence: HADHB NM_000183.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003283
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.45
• Publications: 1 publications found

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), ClinGen, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-26279989-A-T is Benign according to our data. Variant chr2-26279989-A-T is described in ClinVar as Benign. ClinVar VariationId is 203749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00628 (956/152300) while in subpopulation AFR AF = 0.0215 (894/41562). AF 95% confidence interval is 0.0203. There are 7 homozygotes in GnomAd4. There are 444 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHB	NM_000183.3	MANE Select	c.812-5A>T		splice_region intron	N/A	NP_000174.1	P55084-1
	HADHB	NM_001281512.2		c.767-5A>T		splice_region intron	N/A	NP_001268441.1	F5GZQ3
	HADHB	NM_001281513.2		c.746-5A>T		splice_region intron	N/A	NP_001268442.1	P55084-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HADHB	ENST00000317799.10	TSL:1 MANE Select	c.812-5A>T		splice_region intron	N/A	ENSP00000325136.5	P55084-1
	HADHB	ENST00000942431.1		c.896-5A>T		splice_region intron	N/A	ENSP00000612490.1
	HADHB	ENST00000942426.1		c.842-5A>T		splice_region intron	N/A	ENSP00000612485.1

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 949 AN: 152182 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00239 AC: 599 AN: 251016 AF XY: 0.00223

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.000984

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000979 AC: 1423 AN: 1452982 Hom.: 9 Cov.: 28 AF XY: 0.00111 AC XY: 802 AN XY: 723258

African (AFR) AF: 0.0197 AC: 655 AN: 33256

American (AMR) AF: 0.00110 AC: 49 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00672 AC: 578 AN: 85950

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.000241 AC: 1 AN: 4156

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1105842

Other (OTH) AF: 0.00220 AC: 132 AN: 59968

GnomAD4 genome AF: 0.00628 AC: 956 AN: 152300 Hom.: 7 Cov.: 32 AF XY: 0.00596 AC XY: 444 AN XY: 74474

African (AFR) AF: 0.0215 AC: 894 AN: 41562

American (AMR) AF: 0.00144 AC: 22 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.000387 Hom.: 0

Bravo AF: 0.00696

Asia WGS AF: 0.00808 AC: 31 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Mitochondrial trifunctional protein deficiency (2)
-	-	1	Mitochondrial trifunctional protein deficiency 2 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.13
DANN	Benign	0.57
PhyloP100		-1.5
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.028
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

Other links and lift over

dbSNP: rs72851534; hg19: chr2-26502857;