rs1056471

Variant names:

• chr2-26290089-G-C
• rs1056471
• NM_000183.3:c.*136G>C

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.868
• Publications: 14 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), PanelApp Australia, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
HADHB	NM_000183.3	c.*136G>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000317799.10	NP_000174.1
HADHB	NM_001281512.2	c.*136G>C		3_prime_UTR_variant	Exon 15 of 15		NP_001268441.1
HADHB	NM_001281513.2	c.*136G>C		3_prime_UTR_variant	Exon 17 of 17		NP_001268442.1
HADHB	XM_011532803.2	c.*136G>C		3_prime_UTR_variant	Exon 16 of 16		XP_011531105.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HADHB	ENST00000317799.10	c.*136G>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_000183.3	ENSP00000325136.5

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

African (AFR) AF: 0.882 AC: 15227 AN: 17266

American (AMR) AF: 0.635 AC: 26754 AN: 42114

Ashkenazi Jewish (ASJ) AF: 0.905 AC: 18619 AN: 20566

East Asian (EAS) AF: 0.162 AC: 5719 AN: 35300

South Asian (SAS) AF: 0.848 AC: 57743 AN: 68110

European-Finnish (FIN) AF: 0.941 AC: 37788 AN: 40146

Middle Eastern (MID) AF: 0.932 AC: 3225 AN: 3462

European-Non Finnish (NFE) AF: 0.933 AC: 328296 AN: 351750

Other (OTH) AF: 0.867 AC: 28166 AN: 32498

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

African (AFR) AF: 0.883 AC: 36698 AN: 41558

American (AMR) AF: 0.739 AC: 11294 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 3135 AN: 3470

East Asian (EAS) AF: 0.185 AC: 955 AN: 5168

South Asian (SAS) AF: 0.817 AC: 3947 AN: 4830

European-Finnish (FIN) AF: 0.938 AC: 9959 AN: 10616

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.933 AC: 63503 AN: 68032

Other (OTH) AF: 0.861 AC: 1818 AN: 2112

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mitochondrial trifunctional protein deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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