rs1056471

Positions:

• chr2-26290089-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000183.3(HADHB):​c.*136G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 763,492 control chromosomes in the GnomAD database, including 293,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (59285 hom., cov: 33)
  • Exomes 𝑓: 0.85 (233964 hom.)
• Consequence: HADHB NM_000183.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.868

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 2-26290089-G-C is Benign according to our data. Variant chr2-26290089-G-C is described in ClinVar as [Benign]. Clinvar id is 335410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HADHB	NM_000183.3	c.*136G>C		3_prime_UTR_variant	16/16	ENST00000317799.10
HADHB	NM_001281512.2	c.*136G>C		3_prime_UTR_variant	15/15
HADHB	NM_001281513.2	c.*136G>C		3_prime_UTR_variant	17/17
HADHB	XM_011532803.2	c.*136G>C		3_prime_UTR_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HADHB	ENST00000317799.10	c.*136G>C		3_prime_UTR_variant	16/16	1	NM_000183.3	P1

Frequencies

GnomAD3 genomes AF: 0.870 AC: 132313 AN: 152162 Hom.: 59230 Cov.: 33

Gnomad AFR AF: 0.883

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.739

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.817

Gnomad FIN AF: 0.938

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.933

Gnomad OTH AF: 0.862

GnomAD4 exome AF: 0.853 AC: 521537 AN: 611212 Hom.: 233964 Cov.: 6 AF XY: 0.859 AC XY: 286689 AN XY: 333710

Gnomad4 AFR exome AF: 0.882

Gnomad4 AMR exome AF: 0.635

Gnomad4 ASJ exome AF: 0.905

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.848

Gnomad4 FIN exome AF: 0.941

Gnomad4 NFE exome AF: 0.933

Gnomad4 OTH exome AF: 0.867

GnomAD4 genome AF: 0.870 AC: 132427 AN: 152280 Hom.: 59285 Cov.: 33 AF XY: 0.862 AC XY: 64218 AN XY: 74470

Gnomad4 AFR AF: 0.883

Gnomad4 AMR AF: 0.739

Gnomad4 ASJ AF: 0.903

Gnomad4 EAS AF: 0.185

Gnomad4 SAS AF: 0.817

Gnomad4 FIN AF: 0.938

Gnomad4 NFE AF: 0.933

Gnomad4 OTH AF: 0.861

Alfa AF: 0.906 Hom.: 7841

Bravo AF: 0.850

Asia WGS AF: 0.585 AC: 2038 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Mitochondrial trifunctional protein deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.8
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs1056471; hg19: chr2-26512957; COSMIC: COSV58546186;